Alzheimer's Disease Cell Bio


Alzheimer’s Disease (AD) was first introduced in 1906 by Alois Alzheimer as a rare disorder.[1] Currently, AD is responsible for 60-80% of all cases of dementia[2] and nearly 5 million Americans are living with the disease.[1] That number is expected to double by 2050 as life expectancy continues to increase and the baby boomers age.[1][2][3] The likelihood of developing the disease increases with age for both males and females,[2] although approximately two thirds of individuals affected by AD are women.[2] The danger zone for developing AD is 65 years of age or greater, with adults aged 85 years or older having a 25-50% chance of developing the disease.[1][2] In individuals aged 95 and older, over 95% have the disease.[4] Data from 2010 revealed that AD was the 6th leading cause of death in the United States[3] and was the only one in the top 10 that cannot be effectively managed or cured by medical management.[5] Mortality data in the United States for 2011 has not yet been published.

The specific cellular mechanisms of AD pathology are a focus of current research. Significant developments have been made in the past decade; however there is still a lack of understanding of many of the cellular mechanisms and the interactions between the pathways.[2] It is important to consider that AD can only be definitively diagnosed post-mortem. This also limits the amount of research involving human subjects. Based on the current evidence, the two hallmark characteristics of AD include intracellular neurofibrillary tangles and extracellular amyloid beta senile plaques in the brain.[2] These two features are involved in the inflammatory response, apoptosis, mitochondrial dysfunction and cerebral amyloid angiopathy associated with AD. Further explanation of these topics will be addressed on this page along with the other known cellular mechanisms.


Figure 1. Estimated Increase in Alzheimer's Disease Prevalence in the United States from 2010 to 2025 (Figure Source)

Clinical Presentation

AD presents as a gradual decrease in cognition, with a significant impact on memory.[6] Initially, individuals with AD experience difficulty with learning and remembering recent or new information.[6][7] As the disease progresses, difficulty with decision making, abstract reasoning, writing, communicating, processing visuospatial information, and remembering remote information may become evident.[6][7] Additionally, some individuals develop neurological symptoms, such as seizures, loss of bladder control, increased muscle tone, and difficulty with mobility, in the advanced stages of the disease.[6][8] Changes in mood, behavior, or personality are also common occurrences with AD.[6][8] As cognitive impairments become more severe, they typically cause difficulty with work performance, socialization, and household management.[6] Eventually individuals with AD are unable to function independently and require full-time supervision.[7][9] Lack of mobility in the advanced stages of the disease results in increased susceptibility to infections, such as pneumonia, and malnutrition which are common causes of death among these individuals.[9]

Disease Progression

Stages of Alzheimer’s Disease: The following stages of AD are based on a system developed by Barry Reisberg, M.D. who is the clinical director of the New York University School of Medicine’s Silberstein Aging and Dementia Research Center.[5]

  1. No cognitive impairment: Individuals demonstrate no impairments and medical interview provides no evidence of AD.
  2. Very mild decline: Individuals begin to have memory lapses but may still be not be evident during medical interviews or family/friends.
  3. Mild cognitive decline: (early stage AD) At this stage, family and friends begin to notice impairments. Deficiencies may be measurable to clinical testing and during medical interview.
  4. Moderate cognitive decline: (early stage AD) Individuals demonstrate clear cut impairments.
  5. Moderately severe cognitive decline: (mid-stage AD) Large gaps in memory and cognitive function. May require some assistance for day to day functioning.
  6. Severe cognitive decline: (mid-stage AD) Continues to present with memory impairments with possible changes in personality and require assistance for daily activities. During this stage, the individual may lose awareness of recent experiences and forget names of close family/friends; however able to distinguish familiar from unfamiliar faces.
  7. Very severe cognitive decline: (late stage AD) Impaired ability to respond to the environment, ability to communicate and overall motor control. Require assistance with majority of ADLs including toileting and eating. They demonstrate gradual deterioration of motor control.

Risk Factors

The main risk factor for developing AD is increasing age, with those aged 65 and older at greatest risk.[9] Younger individuals may also develop the disease, however, this is often the result of genetic mutations which will be discussed within the genetics section of this page. Other risk factors for AD include family history, mild cognitive impairment, traumatic brain injury or other head trauma, low educational level, reduced cognitive reserve capacity of the brain, and cardiovascular disease risk factors including high cholesterol, type 2 diabetes, sedentary behavior, obesity, and smoking.[1][9] Factors that may help prevent AD include regular physical activity, NSAID use, consumption of foods containing omega 3-fatty acids, high educational level, limited use of alcohol, and adequate intake of vitamins including vitamins C, E, B6, B12, and folate.[4]

Types of AD

Researchers have discovered two distinct types of AD: familial AD and sporadic AD.[2] The two types are distinguished by their onset periods and family history.[10] Specific neuropathologic features, such as plaque formation and neurofibrillary tangles, are present in both types of the disease.[10]

Familial AD (FAD)

This type of the disease is much rarer and is also known as early-onset AD because it can begin as early as the second decade of life.[2][10] FAD is inherited through mutations in the genes for amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2).[10][11] Each of these genes encode proteins that are involved in the production of the amyloid-β peptide.[11] The discovery of these genetic mutations has allowed researchers to create transgenic animal models that display important aspects of the disease and serve as the basis of AD research.[12] These mutations will be discussed in further detail within the genetics section of this page.

Sporadic AD

This type is also known as late-onset AD (LOAD) and is usually diagnosed after age 65.[2] Sporadic AD is much more common than FAD and has been estimated to account for up to 90% of cases.[10] This type of the disease often does not show a family history and is most likely caused by risk alleles (alternative forms of a gene that are associated with increased risk for disease) across various genes involved in amyloid-β production, aggregation, and degradation.[11] The apolipoprotein E (ApoE) gene on chromosome 19 (specifically ApoE4) has been demonstrated to represent a major genetic risk factor for this type of AD.[2][13] One copy of this gene leads to a 3-4 times increased risk and two copies of the gene leads to a 15-19 times increased risk.[2] The gene also lowers the age of onset by 10 years per allele.[2] Other genetic risk factors include mutations to the following: sortilin-related receptor 1 gene, clusterin, and the complement component receptor 1.[13][14]


Amyloid Precursor Protein (APP)

The amyloid precursor protein (APP or AβPP) contains the amyloid-β (Aβ) peptide which is found in the plaques of individuals with AD.[2] It has been estimated that APP mutations cause between 10% to 15% of early-onset FAD cases.[6] In 85 families affected by FAD, more than 32 APP mutations have been discovered.[6] Among these mutations are the London (V717I), Swedish (K670N/M671L), Dutch (E693Q), Indiana (V717F), Florida (I716V), Iowa (D694N), Arctic (E693G), Australian (L723P), and Belgian (K724N) mutations.[12][15] The first mutation discovered, the London mutation, is located near the γ-secretase cleavage site in the transmembrane domain of APP and results in a substitution of valine to isoleucine at codon 717.[16] This mutation causes increased deposition in the brain, formation of senile plaques and neurofibrillary tangles, and cerebral amyloid angiopathy (CAA).[12] The Swedish mutation results in a double amino acid substitution of lysine to aspartic acid and methionine to leucine at codons 670 and 671 of APP near the Aβ domain.[16] In vitro, this mutation causes increased cleavage of APP by β-secretase and results in greater levels of Aβ42 in the brain.[12] A commonly used transgenic mouse model of AD, called Tg2576, expresses APP with the Swedish mutation.[12] Like the London and Swedish mutations, the majority of APP mutations are located near the cleavage sites of enzymes involved in APP processing and subsequent generation of Aβ.[6][18] They often result in increased expression of Aβ42 which is more toxic than other forms of the peptide.[6][18]

Presenilin 1 and 2 (PS1 and PS2)

PS1 and PS2 are proteins with numerous transmembrane domains that can be found in the endoplasmic reticulum, Golgi apparatus, and nuclear envelope.[16][19] Within the brain, higher expression of the presenilins has been noted in the cerebellum and hippocampus.[15] The genes for PS1 and PS2 have a similar structure and are located on chromosome 14 (PS1) and chromosome 1 (PS2).[15][16] These proteins are thought to play a role in signaling pathways, cell death, and initiating the response to unfolded proteins.[18] They are also an important part of the γ-secretase complex that is involved in APP processing.[20]

PS1 mutations are the primary cause of early-onset FAD.[6] Currently, more than 176 PS1 mutations have been identified in 390 families.[6] Individuals carrying a PS1 mutation typically develop more severe forms of AD and display symptoms at an earlier age than those carrying PS2 mutations.[6] Most PS1 mutations are missence mutations, meaning that they cause amino acid substitutions, and are located in the transmembrane domains of the protein.[6][16] In comparison to PS1, PS2 mutations are a much rarer cause of early-onset FAD.[6] At this time, only 14 PS2 mutations have been identified in 6 families.[6]

PS1 mutations are thought to influence γ-secretase cleavage of APP resulting in increased production of the long form of the peptide.[6][16] This is in agreement with studies involving cultured cells and AD mouse models that have shown higher levels of 42 in the presence of presenilin mutations.[19][15] Compared to PS1 and PS2 wild-type cells, cells expressing PS1 and PS2 mutations display a 1.5 to 5 fold increase in 42 concentration in media.[18] Researchers are uncertain whether this change in protein expression is due to increased production of 42,decreased production of 40, or a combination of both.[6] In addition to their effect on Aβ, presenilin mutations have also been associated with increased cleavage by the capsases which are enzymes involved in cell death.[16]

Apolipoprotein E (apoE)

ApoE is a polymorphic (capable of existing in more than on form) protein that consist of 299 amino acids. [22] The gene that encodes apoE is located on the 19 chromosome. [22], [23], [24], [25] It is now known that this process can involve 1 of 3 different alleles (epsilon2, 3, 4). [22], [23], [26], [27]) As a result, the amino acid sequence slightly varies and one of three major isoforms (apoE2, apoE3, and apoE4) is created. [22], [23] These isoforms differ at only two amino acids sites (may also be referred to as residues) the 112th and 158th. [22] ApoE4 has an arginine amino acid at both sites. [22] It is hypothesized that the having an arginine at 112, reduces apoE4’s stability making it more prone to pathological conformation when compared to the other isoforms. [22]

Astrocytes are the primary producer of apoE in the CNS. [22] It is believed that neuronal expression of apoE occurs in the response to neuronal damage, because a vital role of ApoE in the CNS is to assist in the processes of neuron remodeling and repair via its lipid transport function. [22] ApoE2 and apoE3 have proven to be much better at maintaining neuronal cells integrity compared to apoE4. [22] If fact apoE4 is so susceptible to breakdown it often becomes detrimental to the cause. [22] The figure below provides a nice visual of apoE functional process and where breakdowns commonly occur.


Figure 2. 1) Enhanced Aβ production 2) Potentiation of Aβ42 lysosomal leakage & Apoptosis 3) Enhanced proteolysis resulting in increase neurotoxic apoE4 fragments in the cytosol(Figure Source)

ApoE4 has widely been acknowledged as a genetic risk factor for AD. [22] In fact, an article by Mahley et al.,[22] suggest that in some populations 40-80% of the individuals diagnosed with AD possess at least one epsilon4 allele. Despite its strong link to AD, the exact mechanism remains relatively ambiguous. [22] Several mechanism have been postulated, see Table 1:

Table 1: Synthesis of some know effects associated with apoE4 and insight into the proposed mechanisms.

Detrimental Effect Proposed Mechanism
Inhibits neurite outgrowth When a neuron is injured the amount of apoE in circulation is increased.[28] It is hypothesized that this surge is the bodies effort to help in repair, but evidence shows that apoE4 is inefficient at this task leaving the neuron ill equipped to fully heal.[28]
Neuroinflammation ApoE in general is thought to have an anti-inflammatory effect.[28] However, some research now suggest [28], that apoE4 may actually have a pro-inflammatory effect, thus making it a detriment to the process.
Stimulates tau phosphorylation The research behind this proposed effect is far less extensive [28], but the current hypothesize is that apoE4s bond with tau is not sufficient enough to prevent over phosphorylation.
Neurodegeneration It has been reported [28], that fragments of apoE4 that are left behind following the breakdown of the protein may be toxic resulting in cytoskeletal and mitochondrial dysfunction.
Ab Clearance Studies suggest [28], that apoE is heavily involved in the clearance of Ab through several process, such as; endocytosis and transport across the blood brain barrier.
Ab Deposition Current in vitro studies [28], have found that all the apoE isoforms have bonding sites for Ab and that apoE4s bond seems to be the weakest therefore diminishing its ability to regulate Ab aggregation. Some of these studies [28], also indentified apoE4 as having an proliferating effect of the development of Ab fibrils.

Cellular Mechanisms

Many unnatural cellular events occur during AD. Some of them are discussed here.

Amyloid-beta Plaques

Amyloid Precursor Protein (APP)

The amyloid precursor protein (APP or AβPP) contains the amyloid-β (Aβ) peptide which is found in the plaques of individuals with AD.[20][21][30] This protein is part of a family of transmembrane proteins that includes the amyloid precursor-like proteins (APLP1 and APLP2).[20][21] Proteins within this family exhibit large domains outside the cell and are processed in a similar manner.[20][21] APP, APLP1, and APLP2 single knockout mice are viable which suggests that the functions of these proteins may overlap.[30] However, double or triple knockouts of APP/APLP2, APLP1/APLP2, or APP/APLP1/APLP2 is lethal.[30]

While the APP, APLP1, and APLP2 proteins contain several similar domains, the domain is only found within APP.[20][21] The length of APP varies between 695 to 770 amino acids.[2] Although 8 isoforms of APP exist, APP695, APP751, and APP770 are the most common.[20][21] Neurons produce large quantities of APP and process it quickly through one of two pathways that will be discussed below.[21] APP is primarily located within the plasma membrane but it is also found in the trans-Golgi network (TGN), endoplasmic reticulum (ER), and in the membranes of endosomes, lysosomes, and mitochondria.[2][13] Currently, the exact physiological function of APP is not fully understood.[20][21] It is thought to play a role in cell growth, formation of new synapses, differentiation of neurons, cell adhesion, calcium metabolism, and protein trafficking.[2][20][21] Structurally, APP consists of a long N-terminal domain outside the cell, transmembrane domain, and a short C-terminal domain inside the cell.[2] The domain of APP extends from the N-terminal into the transmembrane region.[2][12]

APP Processing

APP may be processed via a non-amyloidogenic pathway that prevents Aβ formation or an amyloidogenic pathway that generates Aβ.[2][15] Refer to Figure 3 below as a visual aid for understanding these pathways.

  • Non-amyloidogenic Pathway: APP is primarily processed through this pathway in peripheral cells.[17] In the non-amyloidogenic pathway, APP is cleaved by α-secretase followed by γ-secretase.[20][21][30] This process occurs primarily on the cell surface.[21] Cleavage by α-secretase occurs within the domain which prevents formation and releases the extracellular secreted APP α (sAPPα) fragment.[2] Researchers have suggested that sAPPα protects neurons, regulates stem cell production, plays a role in brain development, and promotes the formation of synapses and cell adhesion.[20][30] The remaining C-terminal fragment (CTF-83) of APP then undergoes either lysosomal degradation or γ-secretase cleavage which generates p3 and the APP intracellular domain (AICD).[2] The p3 fragment degrades quickly and is believed to lack any important physiological functions.[20][30] The AICD is thought to regulate transcription and intracellular trafficking.[21]
  • Amyloidogenic Pathway: APP is primarily processed through this pathway in neuronal cells and, to a lesser extent, in peripheral cells. [17] In the amyloidogenic pathway, APP is cleaved by beta-site APP cleaving enzyme 1 (BACE1) followed by γ-secretase.[20][21][30] This pathway primarily occurs in the endosomal compartment and TGN.[30] Cleavage of APP by BACE1 releases the extracellular secreted APP β (sAPPβ) fragment which is thought to serve as a ligand for Death Receptor 6 and assist with axon pruning and cell death.[20][21][30] The remaining C-terminal fragment (CTF-99 or CTF-89) of APP is cleaved by the γ-secretase complex which generates peptides and the AICD.[21][30] The site of γ-secretase cleavage within the transmembrane domain of APP can vary and determines the type of Aβ that is produced.[20] After it is produced, is usually secreted into the extracellular space via exocytosis.[21][30] The function of and its role in AD pathogenesis will be discussed in further detail below. As mentioned previously, AICD is thought to regulate transcription and intracellular trafficking.[21]

Figure 3. A.) APP Structure and Cleavage Sites B.) Non-amyloidogenic Pathway C.) Amyloidogenic Pathway(Figure Source)

Enzymes Involved in APP Cleavage

  • Beta-site APP cleaving enzyme 1 (BACE1): This is a transmembrane β-secretase enzyme that frees the sAPPβ fragment when it cleaves APP.[21] It is located in lipid rafts primarily within the TGN and endosomal compartment.[30] BACE1 activity has also been detected in the lysosomal system and the ER.[19] Activity of this enzyme is thought to be the main factor in determining the amount of that is generated.[20] Cellular stress has been associated with an increase in BACE1 expression.[30][29] Therefore, increases in stress associated with aging may trigger an increase in BACE1 levels and Aβ production.[29] A recent study showed that BACE1 levels also increase in response to amyloid plaques.[29] This study found increased BACE1 levels around amyloid plaques in two APP transgenic mouse models.[29] The researchers suggest that a positive feedback loop occurs in AD in which Aβ plaques cause BACE1 levels in surrounding neurons to increase resulting in further increases in Aβ production and amyloid deposition.[29] It has been reported that BACE1 expression and enzymatic activity nearly doubles in the frontal cortex of patients with AD.[17] A significant increase has also been found in the temporal cortex and hippocampus of these patients.[17]
  • α-secretase: This enzyme cleaves APP at the plasma membrane surface and releases the sAPPα fragment.[21][30] Activity of this enzyme has been associated with the ADAM (a disintegrin and matelloproteinase) family of proteases, primarily ADAM 9, 10, and 17.[21] Since it cleaves APP within the domain, α-secretase prevents Aβ formation.[21] A mouse model of AD has shown that increased expression of ADAM 10 reduces production of Aβ, formation of amyloid plaques, and cognitive impairments.[30]
  • γ-secretase: This multiprotein complex requires the interaction of presenilin 1 (PS1) or presenilin 2 (PS2), nicastrin (Nct), anterior pharynx defective 1 (Aph-1), and presenilin enhancer 2 (Pen-2).[21] Each of these components is required for normal enzymatic activity of γ-secretase.[34] As mentioned previously, PS1 and PS2 mutations disrupt activity of the γ-secretase complex and lead to FAD.[6] The complex is mainly found in the ER, TGN, and endocytic compartments.[34] It complements the activity of α-secretase and BACE1 by cleaving the remaining carboxyl terminal fragments (CTFs) of APP.[20][21] In addition to releasing the intracellular domain of APP (AICD), cleavage of the C-terminal produces p3 following α-cleavage and following β-cleavage.[20]

Figure 4. Enzymes Involved in APP Processing (Figure Source)

Amyloid-beta (Aβ)

Aβ is the protein that is the major component of plaques[2] that are found both intracellularly and extracellularly in AD.[35] 42 is considered to be one of the main culprits of these plaques[2] because it oligomerizes more quickly than other forms.[31] Aβ is derived from the cleavage of APP,[2][31] is naturally occurring, and is found in concentrations of about 221 mg/g in healthy adults.[2] It is thought to have an important role in learning, memory, cell survival, immune functioning, and cell excitability.[2] In people with AD, concentrations have been found to be as high as 406 mg/g.[2] Concentrations this high can lead to many cellular dysfunctions that will be discussed in later sections. However, the presence of Aβ plaques is not enough to diagnose AD because many people without cognitive decline have been found to have plaques.[1]

The Amyloid Hypothesis: This was developed in the early 1990s and states that Aβ aggregation is the central hallmark of AD and is the cause of AD rather than an effect.[2] Extracellular Aβ deposits may still be a by-product of AD.[13] In this hypothesis Aβ aggregation begins a neurodegenerative “cascade” that results in neuron death (apoptosis) and cognitive impairments.[2] This theory has come to be known as “amyloid cascade hypothesis.”[2][36] According to the cascade hypothesis the primary event that begins AD is the misfolding and aggregation of Aβ into oligomers.[2] However, there remains some controversy over whether Aβ exclusively causes AD.

Common types of Aβ associated with AD: (not all formations of Aβ are equally toxic)[32]

  1. Aβ-40: This protein is more prevalent than Aβ-42 in healthy individuals. [32]
  2. Aβ-42: This protein tends to be more toxic to neurons. It self aggregates, forms oligomers, accumulates into Aβ deposits and is involved with fibrillogenesis.[32] Aβ-42 contains two water repelling amino acids at the end which increases its attraction to itself in water based fluids, therefore increasing tendency to aggregate forming plaques. It can form a stable cluster up to 5-6 proteins.[33] Elevated levels of Aβ-42 compared to Aβ- 40 is crucial for development of Alzheimer’s disease.[34]

*Studies have shown that relatively minor changes in the Aβ-40/Aβ-42 ratio lead to dramatic effects regarding toxicity [32]*

Aβ Degradation: Because Aβ is a naturally occurring protein there are several enzymes within cells that assist with Aβ degradation: insulin degrading enzyme, neprilysin, plasmin, cathepsin, endothelin-converting enzyme, and the matrix-metalloproteinase family.[2][13] However,the concentration of these enzymes has been shown to decrease as the disease progresses.[13] The blood brain barrier serves to regulate the influx and efflux of Aβ, and the liver and kidneys serve to eliminate Aβ in the periphery.[2]

Soluble Aβ oligomers: also called “Aβ derived diffusible ligands” and “natural toxic oligomers”[32] Oligomers are aggregations of a specific number of monomers that form a larger polymer.[2][32] Often oligomers include dimers, trimers, pentamers and globulomers.[2][32]

  • Aβ oligomers can lead to a pathological state by blocking long term potentiation, altering mitochondria function, enhancing oxidative stress, leading to chronic inflammatory response, altering apoptotic mechanisms and impairing cognitive functioning.[2][32][38]
  • Oligomers can demonstrate toxic effects initially on the synapses and later on the neurons.[32] The toxicity in the primary hippocampal neurons can significantly alter cognitive functions including memory and recall. [32]
  • It is unknown as to which form of oligomer mediates toxicity in AD.[38]

A variety of factors can impact the amount of Aβ in the brain including genetics, aging, immune response and enzyme inhibitors.[2] Mutations of specific genes have been linked to elevated amounts of AB-42, more common with familial AD.[2] The body’s ability to remove AB from the brain begins to decline as it progresses in the aging process.[2] Also, specific enzyme inhibitors can change the amount of AB in the brain.[2]

The specific cellular mechanisms involved in Aβ toxicity in the AD brain remains unknown. There are multiple research studies focusing on differing hypotheses including generation of free radicals, soluble Aβ oligomers, inhibition of signal transduction pathways, impact of tau on toxicity, mitochondrial dysfunction, synaptic failure and many more.[39] Further explanation of these will be described later on the page.

Tau - Neurofibrillary Tangles

Tau is a protein in the microtubule-associated protein (MAP) family. [40] It has several physiological functions in healthy axons including microtubule assembly and stability, vesicle transport, neuronal outgrowth and neuronal polarity.[40] This protein can consist of 352 to 441 amino acids and presents in various isoforms in the brain.[2] In humans, the tau gene is positioned on chromosome 17.[40][41] In a normal brain, there is 2-3 moles of phosphate per one mole of tau indicating this amount of phosphorylation is necessary for tau to perform its normal biological functions.[40] Tau phosphorylation is the addition of phosphate to a tau protein through regulation of tau kinases.[2][40]

A key characteristic of AD pathology is intracellular neurofibrillary tangles (NFTs).[2][39] NFTs consist of a cluster of paired helical filaments consisting of hyperphosphorylated tau.[2] Refer to figure below for further explanation of NFT formation. When tau becomes hyperphosphorylated, the ratio of phosphate to tau increases 3-4 fold compared to normal phosphorylation levels.[40] This increased amount of phosphate alters the function of tau.[2][40] The hyperphosphorylation of tau can be a result of upregulation of tau kinases and/or down-regulation of tau phosphatases.[39] This form of tau is insoluble and lacks affinity for microtubules lead to the degradation of the microtubules.[40] The amount of NFTs in the brain has been correlated with AD severity. [39][13] Current research is focusing on the relationship of Aβ and hyperphosphorylated tau in the AD brain.[42]

Tau Axis Hypothesis:
One recent hypothesis regarding the and tau relationship is the Tau Axis hypothesis.[40] This hypothesis proposes that neurons become more susceptible to Aβ toxicity with elevated levels of tau.[40] The foundation for this hypothesis is rooted in the fact that tau becomes more hyperphosphorylated with disease progression and leads to greater dendritic toxicity.[40] This progression ultimately leads to synapses becoming hypersensitive to Aβ toxicity with resulting neuronal degeneration.[40]


Figure 5. Formation of NFTs in AD. In a normal functioning tau protein, tau provides stability for microtubules and demonstrates the appropriate amount of phosphorylation to carry out its functions. As tau become hyperphosphorylated, the functions of tau become altered leading to instability in the microtubules and ultimate degradation. The hyperphosphorylated tau then begin to pair into helical filaments. These filaments begin to cluster and form NFTs. The NFTs are one of the key characteristics of AD. (Figure Source)

Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) associated with AD is defined as accumulation of Aβ in the vasculature walls in the brain [44],[46]. CAA is considered a by many studies as a major contributor to AD; however, CAA should remain a distinct entity from AD as CAA is found in non-demented subjects over the age of 60 years and subjects with AD have been reported with mild or no CAA [45],[46]. Nonetheless, it is important to study as it has been estimate CAA affects 15%-32% of subjects with AD, leading to hemorrhages and cognitive imairments [45].

AD is the most studied form of amyloid-related disorders in humans, with recent findings demonstrating common features among this group of disorders. The common feature includes abnormal folding and accumulation of specific proteins found in each group of dissorders [46]. Research on CAA in AD suggests this accumulation can be caused by Aβ proteins [46]. This build-up limits blood supply causing hypoxia to brain tissue [46]. Chronic hypoxia may lead to oxidative stress which in turn can induce apoptosis and necrois to the area of brain affected [46].

Research suggest patients with both CAA and AD will have greater cognitive impairments than AD patients without CAA [45]. The following Figure, 6., will demonstrate how CAA affects blood supply and lymphatic drainage of the brain and how these factors contribute to the pathogenesis and CAA and AD.


Figure 6. Pathogenesis of CAA (Figure Source)

Mitochondrial Dysfunction and Synaptic Failure

Normal Mitochondrial Metabolism:
Due to the large energy requirement of synaptic functioning, synaptic mitochondria produce a large portion of the reactive oxygen species (or free radicals), known as superoxide anion radicals, inside neurons.[1] Normally, superoxide dismutase enzymes (SOD), specifically SOD2 (inside mitochondria) and SOD1 (in cytosol), convert superoxide to hydrogen peroxide which is then converted to water.[1]

Synaptic Loss in AD:
Synaptic damage and loss in the cortex is considered one of the earliest cellular events in AD.[13] The number of synapses in the brain is severely reduced and may contribute to 20-30% of the brain-weight loss in AD.[14] This correlates highly with cognitive deficits,[2] and, in fact, it is the best correlate that has been found in AD.[13] Although the exact mechanism for synaptic failure remains a mystery, researchers have made good progress toward discovering the cause.

Mitochondrial Dysfunction:
Mitochondrial dysfunction is also considered to be an early event in AD progression and it continues throughout the course of the disease[13] It is believed that mitochondrial dysfunction plays the major role in synaptic failure in AD.[1] There are two types of mitochondria inside the neurons in the human brain.[35] The first type, known as nonsynaptic mitochondria, typically live about 1 month[14] and spend their entire lives in or near the soma. The second type, and the type that appear to be more important in the development of AD[35][14] are called synaptic mitochondria.[35] Synaptic mitochondria are generated in the soma and then are transported to synapses where they become docked to assist with on-site energy provision and Ca2+ modulation.[35] These mitochondria can be trafficked around axons and dendrites as needed.[35] Mitochondria are important for the synaptic transmission process for two main reasons:

  1. Energy production: Synaptic transmission requires lots of energy (ATP) and mitochondria are able to meet the need through aerobic respiration through a process called mitochondrial oxidative phosphorylation.[35][13]
  2. Ca2+ regulation: During synaptic membrane depolarization, Ca2+ is released from the endoplasmic reticulum (ER) into presynapses. The rise in Ca2+ is the initiating step for synaptic vesicle transport, membrane fusion, and reuptake of neurotransmitters. Long lasting Ca2+ stimulation would injured cells so mitochondria serve as the major organelle of Ca2+ reuptake after Ca2+ influx.[35]

Synaptic mitochondria tend to live longer than nonsynaptic mitochondria[14] but that also means that they are generally more vulnerable to cumulative damage.[35] aggregation occurs in synaptic mitochondria before nonsynaptic[35] and, in fact, oligomeric Aβ may prefer synaptic mitochondria because Aβ is enriched at synaptic terminals before leaving the cell.[14] They also have higher levels of cyclophilin D (CypD), which causes them to be more susceptible to Ca2+ insult.[35]

The Calcium Hypothesis:
The relationship between Ca2+ and the amyloidogenic pathway is bidirectional.[36] Increases in Ca2+ can stimulate the metabolism of APP leading to increased production, and the amyloidogenic pathway can lead to remodeling of neuronal Ca2+ signaling pathways (upregulation) resulting in increased mitochondrial Ca2+ levels.[36] This leads to decreased long term potentiation (LTP), increased long term depression (LTD), and apoptosis.[36]

There are two main pathways in which remodeling of Ca2+ signaling occurs.[36]

  1. Ca2+ levels have been found to be higher when plaques are nearby. The cellular prior protein (PrPc) may be a receptor for Aβ (specifically Aβ42) attracting the oligomers to the area. Ca2+ entry (from ER into the cytoplasm) is boosted by the presence of Aβ42 oligomers because they may function either by acting as Ca2+ channels or activating Ca2+ channels,such as NMDA receptors, in the plasma membrane.[36]
  2. During depolarization, increases in Ca2+ release by the ER are caused by increased sensitivity of receptors such as InsP3 due to increased expression of ryanodine receptors (RYR). Ca2+ release at depolarization can also be increased if ER internal stores are unnaturally increased. ER Ca2+ and cytoplasmic Ca2+ levels are usually regulated and balanced by the SERCA pump (pumps Ca2+ into ER) and a passive leak from the ER into the cytoplasm. PS1 has been found to increase SERCA activity creating a Ca2+ influx into the ER. Passive release is also reduced because of calcium homeostasis modulator 1 (CALHM1) polymorphisms. CALHM1 normally promotes entry of Ca2+ into the cytoplasm (from ER), and changes in the gene reduce Ca2+ leakage into the cytoplasm.[36]

Figure 7. Neuronal Ca2+ Regulation Figure Source

The presence of presenilins also contributes to increases in γ-secretase formation when PS1 and 2 are processed in the Golgi. This ultimately leads to increased 42 production and the remodeling of Ca2+ signal pathways continues.[36] This remodeling disrupts the balance between LTP and LTD and can lead to memory loss. Small elevations in cytoplasmic Ca2+ lead to LTD and the destruction of LTP. One of the main LTD-inducing processes is the generation of InsP3 leading to increased cytoplasmic Ca2+ levels. However, large increases in cytoplasmic Ca2+ levels causes LTP by activating a process called AMPA receptor phosphorylation.[36] This process is easily reversible by LTD.[36] Ca2+ remodeling inhibits LTP by upregulating Ca2+-dependent protein phosphatase calcineurin (CN). CN removes AMPA receptors and impedes LTP.[36]

With LTP inhibited, the Ca2+ increases lead to LTD. Excess cytoplasmic Ca2+ results in uptake by the mitochondria[36] because they have a more rapid uptake system than ER.[35] This increase in Ca2+ disrupts the Ca2+ homeostasis within the mitochondria may lead to collapse of mitochondrial membrane potential as well as the release of cytochrome c with plays a major role in neuronal apoptosis. [36]

Ca2+Disturbance Creates Oxidative Stress:
The disturbance of Ca2+ homeostasis is now considered one of the hallmarks of AD and is believed to be directly caused by Aβ oligomers.[2] Since neurotrophic factors such as BDNF are decreased in AD, the adaptive cellular response pathway (ACSRP)(discussed more fully below) fails to control free radical levels[1] and this leads to oxidative stress inside the mitochondria and eventually to neuronal death.[2] The mitochondria in the brain are particularly vulnerable to oxidative stress because of the brain’s high lipid content, high O2 consumption, and low levels of antioxidants.[14][37] Oxidative stress is increased very early on in the course of AD, and may be due to failed ACSRPs.[1] In AD, neuronal mitochondria have been found to create superoxide radicals in their electron transport chains.[14] Early in vitro and in vivo studies point toward factors related to oxidative stress being involved in activating β- and γ-secretases in LOAD.[13]

The Channel Theory:
Also known as the amyloid pore theory, the channel theory states that oligomeric forms channels through cell membranes which allows an unregulated flow of Ca2+ ions into the cell, disturbing homeostasis.[2][14] Besides unregulated Ca2+, Aβ has been found to accumulate in these mitochondria.[2] This change in homeostasis ultimately leads to cellular apoptosis.[2]

In support of this theory, Texel and Mattson[1] report that if Fe2+ or Cu+ are present within the mitochondria, instead of converting hydrogen peroxide to water it will be converted to hydroxyl radical. This radical is very damaging to proteins and lipids and can cause lipid peroxidation.[1] If too much Ca2+ is present it will interact with superoxide and generate peroxynitrite which can also lead to lipid peroxidation.[1] aggregation usually occurs on membranes and results in membrane lipid peroxidation, effectively weakening its plasma membrane redox system ACSRP.[1] This results in generation of aldehyde 4-hydroxynonenal with has several negative cellular effects:

  • Impairs synaptic function and disrupts cellular Ca2+ and energy metabolism by covalently modifying proteins on cysteine, lysine, and histidine[1]
  • Impairs plasma membrane Na+/K+- and Ca2+-ATPases, and glucose and glutamate transporters[1]
  • Energy depletion[1]
  • Neuron degeneration[1]
  • Triggering of apoptosis[1]

associated mitochondrial dysfunction leading to cognitive decline in AD:[35][13]

  • Decreased mitochondrial motility resulting in disorganized synaptic mitochondrial distribution
  • Decreased mitochondrial ATP provision and respiratory function
  • Decreased cytochrome oxidase activity
  • Elevated mitochondria-associated oxidative stress
  • Increased mitochondrial permeability
  • Decreased mitochondrial Ca2+ modulating capacity and Ca2+ accumulation
  • Impaired respiratory function
  • Release of pro-apoptogenic factors from mitochondria
  • Membrane potential collapse
  • Increased free radical production
  • Increased expression of CypD and Aβ-binding alcohol dehydrogenase
  • Increased mitochondrial fragmentation (important event early in apoptosis)[13]


can have toxic effects via direct mechanisms and indirect mechanisms including inducing local inflammation. The specific mechanisms involved in the inflammatory response associated AD pathology remains unclear.[46] However, research has shown that the inflammatory response may be both neurotoxic and neuroprotective.[46] Inflammatory microglia and elevated inflammatory markers are associated with and have been found in AD plaques.[46][47] An alternative complement pathway is associated with the inflammatory response in the AD brain rather than the classic inflammatory response.[47]

For a review of the normal functions of the cellular mechanisms involved in the immune system, click on the following link here.

Cellular Mechanisms:

  • Microglia: Microglia are specialized brain cells similar to macrophages and act as the innate immune system.[47][48][49] They play a crucial role in tissue maintenance and immune system protection in the brain.[48] Microglia are known to be the first cells in the brain to respond to brain injury or infection.[48][49] In the normal brain, the microglia interaction with neurons and other glia allows for suppression of cellular activation to lessen the response to pro-inflammatory signals as well as the general immune response.[48] The presence of Aβ deposition induces a phenotypic activation of microglia.[48] Once the microglia are activated, they recruit astrocytes through secretion of acute-phase proteins and the release of cytokines including IL-1B and TNF-α.[48] Astrocytes respond with additional complement proteins and acute phase proteins including α1-anti-chymotrypsin and α2-macroglobulin. Microglia are a key element of the inflammatory response associated with AD.
  • Astrocytes:Astrocytes are involved in both removal and disintegration in the brain.[49] They are able to provide neuronal support and assemble a protective barrier between the Aβ plaques and neurons.[49] These astrocytes in the brain are able to phagocyte pathological Aβ peptides allowing for a possible neuroprotective impact by limiting exposure of Aβ to neurons.[49] However, astrocytes may also have a neurotoxic impact as it could be a source for Aβ due to release of inflammatory cytokines and nitric oxide in response to chronic stress and inflammation.[49] Research has identified a correlation between the amount of Aβ42 within the astrocytes and the severity of AD pathology.[49]
  • Neurons: Neurons may directly activate pro-inflammatory mediators including inflammatory cytokines (IL-1B, IL-6 and TNF-α) and chemokines.[49] These molecules are all involved in the inflammatory response associated with AD.

Inflammation and AD

Complement Pathway: An absence of immunoglobulins in senile plaques indicates that the classic immune response is not involved with AD pathology.[47] And the absence of classic inflammatory related adhesion molecules in blood vessels indicates no involvement of blood-borne inflammatory cells in response to the injury. [47] A complement pathway is utilized and initiated through activates of C1q receptors. Aβ1-16 has a higher affinity for C1q proteins and therefore complexes containing this segment strongly bind to microglia and thus lead to activation of microglia and result in an inflammatory response. Research has found that 42 also has a high affinity for C1q which can result in activation of microglia leading to the release of membrane attack complexes and free radicals.[47]

Chemokines: Chemokines are able to directly induce chemotaxis, which is crucial for development and normal function of cells.[49] In relation to AD, chemokines directly influence the microglial movement and astrocyte recruitment to sites of neuroinflammation.[49]

  • CXCL1: CXCL1 is a ligand for CXCR2.[50] Both have been present in AB plagues associated with AD pathology. CXCL1 may play a regulatory role in neuronal dysfunction.[50]
  • CXCL12: CXCL12 is a ligand for CXCR4.[50] The CXCL12/CXCR4 pair can impact the pro-inflammatory function as well as neuron and synaptic signaling.[50] Recent research has found a positive correlation between the amount of CXCL12 and learning and memory.[50]

Inflammatory Cytokines: Inflammatory cytokines are released by microglia and astrocytes in the presence of plaques and include several interleukins (IL), TNFα, and TNFβ.[49] They are involved in the regulation of the level (intensity and duration) of the specific inflammatory response.[49][52] In relation to AD, a majority of these cytokines seem to be up-regulated in Alzheimer’s disease compared to individuals without AD or dementia.[52][53]

  • IL-1B: IL-1B can be released from microglia. IL-1B is involved in the regulation of the inflammatory response associated with AD.[51] It is crucial during the initial phase of AD and is associated with up-regulation of the expression of APP.[51]
  • IL-6: Interleukin 6 can be released by microglia and astrocytes. Through inhibition of TNF and IL-1R, IL-6 can hinder the inflammatory response.[51] Conversely, it may also support the inflammatory response by positively impacting chemotaxis.[51] Based on the current evidence, the correlation between IL6 and AD pathology remains unknown.
  • TNF-α: TNF-α can be released by microglia. This is a very important regulatory inflammatory cytokine due to the impact on multiple other inflammatory cytokines.[51] Its over expression is thought to directly lead to neuronal cell death.[51] Up-regulation of this cytokine can lead to amplified development of NFT and AB peptides. [51]

Pattern Recognition Receptors: A number of pattern recognition receptors are found in the microglia and astrocytes in brain cells to function as a defense mechanism.[54] These receptors are able to identify invading pathogen-associated molecular pattern molecules (PAMPs) and damage associated molecular pattern molecules (DAMPs) to allow for activation of the appropriate immune response.[54]


Figure 8.Figure Source

  • Toll-like receptors (TLRs): Microglia contain Toll-like receptors (TLRs) which allow them to detect PAMPs or DAMPS including peptides, oligomers, fibrils and plaques.[54] In AD, TLR4 and TLR2 are the two main TLRs that can recognize Aβ peptides and oligomers. TLR4 can regulate the neurotoxic effect induced by activated microglia. [55] The levels of TLR4 expression have been found to be elevated in animal studies focusing on AD pathology.[48][54] TLR2 is another key signaling receptor in the inflammatory response and in Aβ clearance.[48][54] It has recently been discovered that these TLRs participate in the microglial response to fibrillar forms of Aβ.[48] The TLRs are important for the initiation and activation of multiple intracellular signaling pathways.
  • NOD-like receptors (NLRs): NLRs are proteins that regulate the inflammatory and apoptotic responses within and are involved in non-specific immunity.[54] They are able to sense microbial pathogens in the cytoplasm. Research has shown that they may form Aβ oligomers that activate caspases necessary for inflammatory responses.[54] NOD1 and NOD2 can activate NF-κB signaling which is utilized by inflammatory molecules and leads to the assembly of inflammasomes.[56] Inflammasomes are multiprotein oligomers that contain caspase 1, are involved in inflammatory processes and may induce cell pyroptosis, a part of cellular apoptosis.[57] They can also cause an efflux of K+ and reduction of intracellular K+ concentration that can activate inflammasomes.[54] This may initiate increased inflammatory responses through IL-1β and IL-18 leading to apoptosis due to caspase 1 activation.[54] In relationship to AD, IL-1β and IL-18 are up-regulated in AD.
  • Formyl peptide receptors (FPRs): FPRs are part of a family of G protein coupled receptors involved in chemotaxis, mediating cellular immune response to infection and may suppress the immune system under certain conditions.[58][59] In humans, there are two FPRs including FPRL1 and FPRL2 proteins.[54] FPRL1 are normally present in the human brain at relatively low levels. However, the expression of this protein is significantly upregulated by inflammatory mediators including TNFα, IFNγ and ligands to TLRs and NOD2. Aβ42 can also activate FPRL1 receptors inducing a rapid uptake of Aβ42/FPRL1 complex in microglial cells. Based on this information, Aβ42 can induce chemotaxis of monocytic cells. This allows the Aβ to induce the inflammatory signaling including superoxide radical production and NADPH oxidase. [60] This is supported by the fact that increased levels of FPRL1 have been found in AD plaques. FPRL1 can also have neuroprotective effects when humanin peptides compete for the FPRL1 receptor and are able to inhibit Aβ endocytosis and neurotoxic effects.[54]
  • Receptor of advanced glycation end products (RAGE): RAGE is a transmembrane receptor in the immunoglobulin superfamily.[54] In the brain, there are three isoforms of RAGE present including full length RAGE, soluble sRAGE and dominant negative dnRAGE.[54] NF-κB is the major signaling pathway activated by RAGE.[54] Aβ peptides are RAGE ligands which allow them to perform the following functions; activation of microglia, collaborate with PECAM-1 to enhance migration of circulating monocytes across the brain endothelial cells.[61] This type of trafficking across the BBB may influence the inflammatory response in AD.[61] Based on several mice models, RAGE expression can potentiate neuronal dysfunction in Aβ associated with AD pathology.[62] The combination of NF-κB pathway activation and elevated levels of RAGE ligands (AB peptides) contributes to the chronic inflammation associated with AD.
  • Scavenger receptors: Scavenger receptors are located on the cell surface and are able to identify a variety of ligands.[54] Their main function is to regulate phagocytosis of microbes and recognize internal Aβ fibrils. They are also essential for innate immunity but have pathologic functions too. Scavenger receptors include class A receptors, SR-A1, SR-A2 and MARCO and class B receptors, SR-B1 and CD36. Type A and B receptors can be found in the microglia, astrocytes and vascular cells in the brain. They can directly bond to fibrillar and non-fibrillar AB peptides.[54] The inflammatory effects depend on CD-36. However, CD36 is not found in neurons and therefore has no effect on hyperphosphorylation of tau or development of NFTs.[54][63]
  • Pentraxins: Pentraxins are involved in the acute immunological responses.[54] There are two types of Pentraxins: short and long. The short pentraxins include serum amyloid P component (SAP) and C reactive protein (CRP). CRPs are expressed during the acute stage of tissue injury or inflammation. They are known to perform the following functions: promotes agglutination, bacterial capsular swelling and phagocytosis and activates classical complement pathway. [64]. SAPs are found in all types of amyloid deposits and have important implications in atherosclerosis and amyloidosis. CRP and SAP have been found in plaques and NFT in AD brain. [65] The role of SAP and CRP in the brain is still unknown. However, cell experiments have shown that SAP and CRP are toxic to neurons. [54] The long pentraxins include PTX3 and other neuronal pentraxins (NP1, NP2, NPR and Narp). PTX3 is rapidly produced by several cells in response to primary inflammatory signals. It also has a high affinity to the complement system C1q. [66]. The role of PTX3 is still unknown in AD. [54]

Cyclo-oxygenases (COX-1 and -2)
COX-1 and -2 are known to catalyze inflammatory mediators including prostaglandin (PG) in the cell and are involved in numerous inflammatory activities.[46] In relation to AD pathology, COX-2 mRNA have been shown to increase rapidly in response to inflammatory agents and therefore is considered “pathological enzyme”.[47] Induction of the COX-2 can also result in highly reactive oxygen species which can lead to protein and DNA damage. In AD, expression of COX-2 is increased in the frontal cortex and in CA1 neurons that are destined for apoptotic death which may be an early mechanism for apoptosis in AD.[46][47]


Figure 9. Inflammation and Alzheimer's diseaseFigure Source

Neuroinflammation, vascular inflammation and AD:
Chronic inflammation is characterized by increased plasma concentrations of C reactive protein.[46] This acute phase protein is often associated with elevated risk for atherosclerosis and found in lesions of AD.[46] This inflammation can be the link between vascular abnormalities and AD pathology. A number of studies have shown the presence of inflammatory markers including chemokines, cytokines and activated microglia in the AD brain.[67][68] In a brain with AD, the endothelial cells present with high levels of inflammatory adhesion molecules including monocyte chemoattractant protein-1 (MCP-1), intracellular adhesion molecule-1 (ICAM-1) and cationic antimicrobial protein 37 kDA (CAP37).[46] Significantly higher levels of nitric oxide (NO), thrombin, tumor necrosis factors – gamma (TNF gamma), transforming growth factor- beta (TGF-b), interleukin (IL), IL-1B, IL-6, IL-8, and matrix metalloproteinases (MMPs) are also present in the AD brain.[46] This can contribute to the toxic cycle where inflammation precedes Aβ deposition and Aβ leads to release of inflammatory mediators.

Advantages to inflammatory response:

  • Activated microglia can phagocytose and break down Aβ peptides to prevent aggregation of Aβ peptides and avoid chronic inflammation. They can also eliminate any neutrophil debris or wast in the cell to reduce any further cell damage.[47]
  • Astrocytes can target specific neurons from the Aβ plaques and release appropriate cytokines and growth factors to aid in repair of damaged neurons.[47]

Disadvantages of inflammatory response:

  • Increased amounts of cell injury or death of neurons can occur when the inflammatory response is chronic and uncontrolled in nature.[47]
  • The inflammatory response may be directly correlated with the progression of Aβ plaque pathology.[47]


Apoptosis is an physiological mechanism of cell death that is critical during development. This programmed mechanism allows for a balance between cell death and cell division leading to appropriate development of tissues.[69] The altered ratio of cell death and cell division is common in diseases such as cancer. In relationship to AD, controversy exists regarding the exact mechanism of cellular death between apoptosis and necrosis. [69]

There are two signaling pathways that converge to execute apoptosis:[70]
1. Extrinsic: Cell surface death receptors (subset of TNF-R) are activated by binding to their ligands which leads to clustering of adaptor proteins causing the activation of caspase 8.
2. Intrinsic: Various stress signals impact the mitochondria to cause a leakage of pro-apoptotic factors (cytochrome c and apoptosis-inducing factors). Apoptosomes are formed when cytochrome c binds to Apaf-1 in the presence of ATP. This results in the activation of caspase- 9 leading to activation of the effector capsase 3.
Both pathways ultimately converge throughout the activation of the effector caspase 3 and caspase 7. The activation of these two caspases can lead to apoptosis. Another mechanism for apoptosis is initiated in the endoplasmic reticulum(ER). The ER is stressed which leads to release of capsase-12 causing cell death through apoptosis.[70]

Difference between apoptosis and necrosis
Apoptosis is controlled by genes which are activated by a variety of environmental stimuli including DNA damage, oxidative stress, and exposure to drugs, toxins and hormones.[69] Apoptosis can be viewed as a basic evolutionary selection process of survival of the fittest which only the strong healthy neurons will survive and the weak, unhealthy neurons will die. Apoptosis is differentiated by shrinking of the cells and avoidance of the inflammatory response.[69] Necrosis is not developmentally programmed and is a passive physiological event that arises after spontaneous insult or trauma to the cells.[69] It is distinguished by swelling of cells and mitochondria and is associated with inflammation.[69] The table below provides further details between the two mechanisms.

Table 2. Apoptosis and Alzheimer's Disease [69]

Apoptosis Necrosis
Cell shrinkage Cell swelling
Membrane blebbing Disintegration of membranes
Chromatin aggregation Random degeneration of DNA
DNA-laddering in agarose gel DNA-smear in agarose gel
Formation of apoptotic bodies Cell lysis
Organelles and membranes remain intact Disintegration of organelles
Enzymatic process/caspase-activation Disturbed ion homeostasis
Energy dependent Energy independent
Well-controlled cell death Insult-induced spontaneous cell death
No inflammatory response in situ Inflammation

Apoptosis in AD
Several histopathological studies have found the incidence of apoptosis in a brain with AD can increase 50 fold when compared to age-matched brains without AD.[69] However, other research has reported only necrosis and no apoptotic morphology in AD tissue. This leads to the controversy of the cause of cell death in AD between apoptosis and necrosis. It is known that the activation of caspases leads to cell death through apoptosis. Caspases cause the disintegration of the cell through fragmentation of proteins and DNA. Caspase-3 has been associated with APP processing and cleavage. [69] Caspases attack vital cellular structures and function as a structured operation. Initially, they cut off interaction with surrounding cells, reorganize the cytoskeleton and stop DNA replication. Next, they destroy the remaining DNA, interrupt the cellular structure and induce the cell to activate signals for phagocytosis. This leads to the disintegration of the cell into apoptotic bodies which is a key part of apoptosis.[69]

It has previously been stated that presenilin 1 and 2 genes are associated with familial AD. In vitro studies focusing on apoptosis and AD found, Presenilin 2 overexpression makes the neuronal cells more vulnerable to cell death through apoptosis due to withdrawal of trophic factors. Oxidative stress and mitochondrial dysfunction are other factors that can impact cellular apoptosis. [71] Oxidative stress may trigger apoptosis through stimulation of stress-activated protein kinases including JNK and p38 as well as through an increase in free radicals. Mitochondrial dysfunction will alter calcium homeostasis resulting in the release of pro-apoptotic mitochondrial proteins ultimately leading to cell death.[71] Based on the current research, there are multiple factors and mechanisms that can impact apoptosis in AD.

Lysosome Dysfunction

Normal Lysosome function
Lysosomes play an essential role in digestion, degradation of wastes and removal of damaged organelles.[72][73] They have been described as part of the “digestive system” of the cell.[72] Endocytic and autophagic pathways are often utilized by lysosomes for performance of their cellular functions. [72] The autophagic pathway is a form of cell death in which the cell actively engulfs any waste or debris.[72] The endocytic pathway utilizes multiple cellular compartments to consume molecules from the plasma membrane to recycle them or break them down. This pathways involves early and late endosomes and lysosomes.[72]

Lysosome Dysfunction in AD
Lysosomal dysfunction is evident in AD due to the presence of lysosomal hydrolases found near AB plaques in the brain.[72] The γ-secretase complexes that are involved in Aβ cleavage are embedded in endocytic and autophagic pathways.[72] Therefore, any changes or alterations in the processing of the endocytic and autophagic pathways may lead to altered and possibly neurotoxic AB assembly resulting in AD pathology. Presenilin 1 (PS1) is another possible mechanism of lysosomal dysfunction.[73] PS1 is involved in the multiple parts of the autophagic pathway including lysosomal acidification and proteolysis.[73] A mutation in PS1 may lead to defective proteolysis allowing for further pathological accumulation of AB in the brain.[72][73]

Adaptive Cellular Stress Response Pathways (ACSRP)

Cells naturally respond to stress by activating adaptive cellular stress response pathways (ACSRP) that promote cell repair and survival.[1] Cells increase their resistance to stress, specifically oxidative stress, by producing several growth factors that support neurons:[1]

  • Fibroblase growth factor (FGF2)
  • Nerve Growth Factor (NGF)
  • Brain-derived neurotrophic factor (BDNF)

Normally neurons respond to oxidative stress by upregulating BDNF, FGF2, NGF, and heat shock protein 70 (Hsp70).[1] CREB is activated by increases in Ca2+ and induces BDNF expression.[1] It is likely that that they play a role in the upregulation of antioxidants such as SOD and antiapoptotic proteins such as Bcl-2.[1] BDNF may be a key factor in slowing AD progression due to its activity-dependent nature and its role in synaptic plasticity, learning, and memory. These ACSRPs have been found to be compromised in AD.[1] Other ACSPs that may be vulnerable to AD include antioxidant response systems, protein chaperone systems, and protein degradation pathways.[1]

Molecular Chaperones

Following their synthesis on ribosomes, proteins fold into a three-dimensional structure that is specified by their amino-acid sequence, known as their “native state”.[74] Maintaining this shape is essential for proper protein functioning and cellular homeostasis.[74] If proteins fail to fold properly or become misfolded, due to cellular stress, protein aggregation can occur which may lead to disease.[74][75] Protein aggregation may result in the formation of unordered, soluble oligomers.[74] Proteins in the oligomeric state are considered to be highly toxic and are thought to play an important role in diseases such as AD.[74] Some soluble oligomers may undergo rearrangement to become ordered and stable structures known as amyloid fibrils.[74] Molecular chaperones are proteins that prevent the formation of these toxic species by interacting with other proteins to assist with folding, conformational changes, and transport.[74][75] Two types of chaperones have been described in the literature: “professional” chaperones, such as heat shock proteins (Hsps), and “amateur” chaperones, such as apolipoprotein (ApoE).[76] Professional chaperones assist with protein folding and managing misfolded proteins while amateur chaperones facilitate conformational changes and protein transport.[76] These chaperones come in contact with many proteins involved in AD including APP, PS1, Aβ, and tau.[77]

Heat Shock Proteins (Hsps)

Hsps are divided into two families according to differences in their molecular size and function.[76] Classic Hsps have a higher molecular weight and contain an ATP-binding site which allows them to play an active role in protein refolding.[76] Among these proteins are Hsp90, Hsp70, and Hsp60.[76] Small heat shock proteins (sHsps) have a lower molecular weight, lack an ATP-binding site, and assist the larger Hsps with protein refolding.[76][78] Currently, ten sHsps have been identified including αβ-crystallin, Hsp27, Hsp20, HspB8, and HspB2/B3.[76] During normal cellular conditions, Hsps assist with cellular metabolism and normal protein folding.[76] During stressful cellular conditions, concentrations of Hsps increase to refold damaged proteins, protect against aggregation, and target severely damaged proteins for degredation.[74][78] Increased expression of Hsps in response to cell stress occurs through the activation of heat shock factor (HSF1) which travels to the nucleus to initiate the process of transcription.[77] As seen in Figure 10 below, Hsps recognize and bind to the exposed hydrophobic regions of unfolded proteins, known as “non-native” proteins, to form a complex and block protein aggregation.[74][76] Hsps then utilize ATP to return the proteins to their “native” form.[76] The ubiquitin-proteasome system (UPS) and autophagy system assist chaperones with protein removal in the event of irreversible misfolding or aggregation.[74]


Figure 10. Refolding of Unfolded Proteins by Hsps [76]

Hsp70 receives newly synthesized proteins that are partially folded or unfolded from Hsp40.[74][77] Binding of a substrate to Hsp70 requires ATP hydrolysis of ATP to ADP, a process which is catalyzed by Hsp40.[74] While bound to Hsp70, the substrate is stabilized and unable to aggregate.[74] When the substrate is released from Hsp70, a process which requires ATP binding to the complex, it quickly refolds by burying exposed hydrophobic regions.[74] If the substrate requires more time to fold properly, it will rebind to Hsp70 to remain stabilized while it attempts refolding again or is transferred to a chaperonin, such as Hsp 60.[74] Chaperonins are ringed complexes which enclose the substrate in a “cage” while it undergoes folding.[74] Like Hsp70, the processes of substrate binding and release to chaperonins are regulated by ATP hydrolysis and binding.[74] Hsp90 interacts with various molecules involved in signal transduction downstream of Hsp70.[74] Again the ability of Hsp90 to bind and release substrates is driven by ATP processes.[74] Unlike the other previously discussed Hsps, Hsp90 has been shown to maintain abnormal proteins in a functional state allowing them to aggregate and accumulate.[79] Inhibition of Hsp90, however, activates heat shock factor-1 (HSF-1) which upregulates other chaperones, such as Hsp70 and Hsp40, to reduce cellular toxicity.[79] Hsp90 inhibitors also promote reduced activity and degradation of abnormal proteins stabilized by Hsp90.[77][79] The potential of Hsp90 inhibitors as a treatment for neurodegenerative diseases, such as AD, is currently being explored.[79]

Increased expression of Hsps has been observed in areas of the brain affected by AD.[77][78] Hsps interact with various proteins involved in the disease process including APP, , and tau.[77] Chaperones within the endoplasmic reticulum (ER), primarily the ER isoform of Hsp70, interact with APP to reduce Aβ production.[77] Small Hsps within the cytosol, including Hsp22 and Hsp27, have been shown to bind to Aβ plaques and prevent fibril formation.[77] Additionally, it has been suggested that αβ-crystallin, Hsp20, and HspB8 protect cerebrovascular cells against toxicity caused by Aβ.[76] Large Hsps within the cytosol, including Hsp70 and Hsp90, have also been shown to inhibit Aβ aggregation early in the disease process.[77] With regards to tau, it has been reported that chaperones, including Hsp27 and Hsp70, recognize hyperphosphorylated tau and induce either its degradation or dephosphorylation.[77] Additionally, Hsp70 and Hsp90 have been shown to facilitate proper tau folding and microtubule binding thus preventing aggregation into NFTs.[76][78]

Despite their up-regulation, Hsps are unable to prevent protein aggregation in AD.[76] It has been suggested that chaperones and other elements that help maintain cellular homeostasis become overwhelmed by high levels of “non-native” proteins resulting in disease.[75] Older adults may be particularly prone to developing AD because chaperone expression and activity is thought to become impaired with increasing age.[75][76][78] Increasing age has also been associated with decreased activity of the proteasome which is largely responsible for protein degradation.[78]


Several types of apolipoproteins are expressed in the human brain including apoE, apoJ, and apoD.[28] The three common isoforms of apoE are: apoE2, apoE3, and apoE4.[28][75] These proteins are expressed by astrocytes and microglia and serve a major role in lipid transport and metabolism.[76] As mentioned previously, the ε4 allele of apoE is considered a risk factor for AD while the ε2 allele is considered to be protective against the disease.[28][75] ApoE is thought to assist with the formation of stable Aβ complexes, facilitate Aβ transport and clearance, decrease inflammation, and maintain neuron function.[28] ApoE binds with Aβ on low-density lipoprotein receptor-related protein-1 (LRP-1) forming a complex.[76] Although controversial, it has been suggested that the complex is either degraded in lysosomes or is transported across the blood brain barrier to facilitate clearance of Aβ from the brain.[28] These functions, however, are isoform dependent.[28][76] The apoE4 isoform has been associated with increased amyloid plaque density, decreased Aβ clearance from the brain, reduced neurite outgrowth, greater neurotoxicity, and increased inflammation.[28][76] It has been reported that apoE4 does not bind as tightly to Aβ as the other isoforms which impairs its ability to transport the protein for clearance.[76] It is unclear whether apoE4 increases the risk of AD due to an increase in toxic function, reduction in protective function, or a combination of both.[28]

Neurotrophic Factors (NTF)

Neurotrophic factors (NTF) are small proteins involved in the development, plasticity, and maintenance of brain function.[80][81][82] Given these beneficial roles, NTF are being investigated as a potential treatment for neurodegenerative disorders such as AD.[82] Among the most common neurotrophic factors are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5).[80] NTF are synthesized as precursors, called proneurotrophins (pro-NGF, pro-BDNF, pro-NT-4, pro-NT-3), that become mature through enzymatic cleavage.[80][83] Proneurotrophins have been shown to increase cell death through binding with the p75NTR receptor while mature NTF improve cell survival and function through binding with Trk receptors.[80][82] As seen in Figure 11 below, NTF activate different types of Trk membrane-bound receptors: NGF activates TrkA, both BDNF and NT-4 activate TrkB, and NT-3 activates TrkC.[80][83] Activated Trk receptors subsequently activate the following signaling pathways: Ras/Raf/mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and phospholipase C-γ 1 (PLCγ) which are involved in the survival and growth of neurons.[83][84]


Figure 11. Receptors for Neurotrophic Factors (Figure Source)

Nerve Growth Factor (NGF)

In the brain, NGF is primarily released as its precursor, proNGF.[85] ProNGF is produced in the neocortex and hippocampus and transported to the basal forebrain.[80] Cholinergic neurons in the basal forebrain, which release the neurotransmitter acetylcholine, rely on NGF to maintain their biochemical and structural makeup.[85] These neurons are responsible for providing cholinergic innervation to the hippocampus and cerebral cortex.[85] The NGF precursor is converted to its mature form extracellularly through the conversion of plasminogen to plasmin via activity of tissue plasminogen activator (tPA).[85] The mature form of NGF is responsible for the biological activity of this NTF.[85]

A significant increase in the precursor form of NGF resulting in cholinergic atrophy has been reported in AD.[85] Researchers have attributed these findings to a disruption in the conversion of proNGF to mature NGF due to a decrease in plasminogen and tPA.[85] Additionally, increased degradation of mature NGF has also been reported which further reduces the availability of this form of NGF in the brain.[85] It has been shown that NGF maturation and degradation processes are negatively affected by accumulation of Aβ in AD.[85] Conversely, other studies have reported a decline in NGF within the basal forebrain while levels remain normal in the hippocampus and cortex. [80] [82] Researchers have attributed this finding to a disruption in NGF transport.[80][82] Regardless of the cause of decreased NGF, when cholinergic neurons in the basal forebrain are deprived of this protein they display cell shrinkage, decreased fiber density, and downregulation of certain enzymes including acetylcholinesterase and choline-acetyl transferase.[80] Since these neurons are responsible for providing cholinergic innervation to the hippocampus and cerebral cortex, dysfunction can reduce neural activity resulting in cognitive dysfunction.[82] It has been reported that cholinergic neuron loss provides the best correlation with synaptic failure and cognitive decline observed in AD.[82] Administration of mature NGF is being explored as a treatment method for AD to decrease cholinergic neuron atrophy and restore cognition.[82]

Brain-Derived Growth Factor (BDNF)

BDNF is reported to be the most highly expressed NTF in both immature and mature brains of mammals.[86] In the brain, BDNF is synthesized as the precursor form, proBDNF.[80][86] This precursor is converted to its mature form either intracellularly or extracellulary via enzymatic cleavage.[80][86] BDNF is located in both presynaptic and postsynaptic compartments.[86] This protein has been shown to play an important role in neurogenesis and a type synaptic plasticity known as long-term potentiation (LTP) which is involved in learning and memory formation.[1] [86] BDNF has also been shown to increase glutamate release, an excitatory neurotransmitter, at presynaptic compartments and increase receptors for glutamate, including AMPA and NMDA, at postsynaptic compartments thereby effecting synaptic transmission.[86] Additionally, it has been suggested that BDNF protects against oxidative stress by increasing production of antioxidants such as glutathione peroxide 1 and Bcl-2.[1] These biological functions have been attributed to the activation of TrkB receptors by BDNF leading to various intracellular signaling pathways which will be described below.[86][81] Studies have shown that decreased activity of either BDNF or TrkB results in a significant impairments in LTP, learning, and memory.[1][84]

As seen in Figure 12 below, activation of TrkB initiates the PLCγ, PI3K, and extracellular signal-regulated kinases (ERK) signaling pathways.[86] These pathways ultimately lead to the activation of cAMP-calcium response element binding protein (CREB), a transcription factor that controls the expression of genes involved in neuronal survival and growth, including BDNF.[86] PLCγ becomes activated upon binding to the Trk receptor.[86] This signaling pathway leads to increased intracellular calcium levels via the breakdown of lipids to inositol 1,4,5 triphosphate (IP3) and activation of the calcium calmodulin dependent kinase (CaMKII) which activates CREB.[84][86] PLCγ can also increase intracellular concentrations of diacylglyceral (DAG) which regulates a protein involved in neurite outgrowth called protein kinase C (PKC).[84] The PI3k signaling pathway is activated through Gab1, a protein that functions downstream of the Shc/Grb2/Sos protein complex.[86] This pathway leads to activation of the protein Akt which suppresses apoptosis and may also activate CREB.[84][86] The ERK signaling pathway is activated by either the P13k pathway or the Ras/Raf/MEK cascade which also functions downstream of the Shc/Grb2/Sos protein complex.[86] This pathway leads to activation of CREB as well as the mammalian target of rapamycin (mTOR) which enhances protein translation.[86] Additionally, it has been reported that the ERK signaling pathway is essential for neurogenesis and may inhibit proteins involved in apoptosis.[84]


Figure 12. Signaling Pathways Associated with TrkB Activation by BDNF (Figure Source)

In AD, decreased mRNA and protein levels of BDNF have been observed in the hippocampus and areas of the cerebral cortex including the temporal and frontal lobes.[80][81] A reduction of the TrkB receptors has also been reported in the hippocampus and frontal cortex in association with AD.[80] These findings are primarily based on studies of post-mortem brains of individuals with AD.[81] Interestingly, a recent study demonstrated that individuals in the early stage of AD display higher BDNF serum concentrations than both healthy controls and those in the more advanced stages of the disease.[87] Based on this finding, the researchers proposed that BDNF is upregulated early in the disease course and decreases as the disease progresses.[87] A significant correlation between BDNF serum concentrations and scores on the Mini-Mental State examination was also found in this study.[87] In addition to decreased BDNF expression, AD has also been associated with impaired BDNF function caused by Aβ.[81] This peptide has been shown to disrupt the pathways activated by BDNF including CREB and LTP.[81] In culture, Aβ has also been shown to downregulate both BDNF and CREB.[80]

Neurotrophin-3 (NT-3) and Neurotrophin-4/5 (NT-4/5)

In contrast to other NTF, NT-3 mRNA and protein levels are unaffected by AD.[80] In cortical neuron cell cultures, NT-3 has been shown to reduce Aβ toxicity by preventing cleavage by caspase-8, caspase-9, and caspase-3 which are involved in apoptosis.[80] NT-3 also causes increased expression of neuronal apoptosis inhibitory protein-1.[80] With regards to NT-4/5, protein levels are mildly reduced in the hippocampus and cerebellum while mRNA levels remain unchanged.[80] Through activation of the TrkB receptor, this protein assists with Tau dephosphorylation along with BDNF.[80]

Decreased Cellular Function with Natural Aging

There are many normal changes to cellular functioning as a person ages. Some of these changes may contribute to the development of cognitive impairments by providing a figurative foothold.

  • Natural antibodies (such as NEP and IDE) against oligomeric Aβ and its plaques have been found to decrease with age[2][13]
  • Decreased plaque clearance due to reduced efficiency of the immune system that occurs with aging[2]
  • Increased mitochondrial oxidation[2]

Brain Areas Affected

AD affects areas of the brain involved in learning and memory including the hippocampus, amygdala, and areas of the temporal, frontal, and parietal lobes.[2] AD is clinically diagnosed by progressive memory impairment and reduced size of the hippocampus, temporal, and frontal lobes.[1] An MRI is usually used to detect the changes in size.[1] Research has found neocortical functions are more affected in early onset of Alzheimer’s disease/ familial (FAD) and learning is more affected in late onset of Alzheimer’s disease (LOAD) [89].

What is unknown and is still being researched is whether or not grey matter atrophies before or after white matter degenerates. Some studies suggest the white matter, or neural networks, degenerates first [90], [95] while other studies support gray matter atrophies before white matter degeneration [93], [94]. Studies supporting GM becomes damaged first, have found structural changes in the GM, in the form of hypometbolism/oxidative stress, without functional changes being present in their subjects [93],[94]. These studies suggest GM atrophy disrupts white matter tracts via retrograde degeneration [90].

However, a recent study, supporting neural damage appeared first, found neural disconnection in mild cognitive impairments (MCI) subjects, who did not demonstrate the presence of GM atrophy [90]. The damaged neural networks were present between the anterior cingulate and superior frontal gyrus as well as the hippocampus and frontal, temporal, and posterior GM cortexes [90]. The evidence that supports GM atrophy occurs second came from a follow-up MRI study a year later. This follow-up found 40% of the MCI subjects had GM atrophy, suggesting disconnect may be the first stage of AD [90].

While theories continue to be studied on the order of neural disconnection and GM atrophy, research is suggesting damage in the brain may be a product of decreased metabolism, or hypometabolism, via oxidative stress [90],[91], [92]. A study has found that oxidative stress damages nucleic acids, lipids, and proteins in the brain leading to decrease metabolism, neural damage, and potentially complete disruption (singh). Increases of oxidative proteins have been reported in the hippocampus, frontal, parietal and temporal lobes in subjects with AD [91]. To read more about oxidative stress and how this damage occurs, read our section on Adaptive Cellular Stress Response Pathways (ACSRP).

Brain Areas Affected in FAD[88]

  • Higher prevalence of language impairment or other neocortical functions[89], [98]
  • Faster cognitive deterioration [96]
  • More severe perfusion and metabolic deficits in the temporal and parietal areas [97], [98]
  • Greater grey matter atrophy [99]

Cortical pattern matching analysis showed that in FAD statistically significant grey mass reduction was widespread, involving the frontal, temporal, parietal and occipital cortex including the posterior cingulate and the retrosplenial region, and sparing only the somatosensory and primary visual cortex, the anterior cingulate gyrus and the orbitomesial cortex[88]. Conversely, in LOAD patients statistically significant grey mass reduction was located in the temporal, retrosplenial cortex, and the temporoparietal junction [88].

The different degree of Grey Matter loss in FAD and LOAD[88]

  • FAD, grey matter loss of 25% or more mapped to large neocortical areas affecting all lobes, with relative sparing of the left frontal and anterior temporal lobes, and preservation of primary sensory, motor, and visual cortex, and anterior cingulate and orbital cortex
  • LOAD, grey matter loss was diffusely milder (below 15%), with losses between 15 and 20% confined to part of the temporoparietal and retrosplenial cortex. Losses reached 25% in restricted areas of the medial temporal lobe and right superior temporal gyrus
  • FAD patients, on average, have more severe grey matter atrophy than LOAD patients matched for dementia severity, and that atrophy has a topographic specificity, being more severe in neocortical areas in FAD, and in the hippocampus in LOAD
  • In both FAD and LOAD. The posterior limbic system is comprised of the posterior cingulate gyrus and its most strictly interconnected structures, i.e. the temporoparietal, retrosplenial and entorhinal cortex and the hippocampus.
  • the ventromedial prefrontal and anterior cingulate cortex, belonging to the anterior sector of the limbic system based on their cingulate connectivity, are selectively spared in both FAD and LOAD

Neurochemical and neuroimaging studies support the view that plaques and tangles might deposit earlier or more heavily in the neocortex and later or less heavily in the hippocampal regions in FAD, and the opposite might occur in LOAD [100]. Choline acetyl-transferase has been found to be significantly lower in FAD than in controls in extensive brain areas including the frontal and temporal cortex, while choline acetyl-transferase activity in LOAD was significantly lower than in age-matched controls only in the hippocampus [100]. Another study assessing choline acetyl-transferase as well as aminobutyric acid (GABA) and somatostatin found widespread reductions in the concentration of all neurotransmitters in FAD, while in LOAD the deficit was confined to the cholinergic enzyme in the temporal lobe and hippocampus [101]. More recent studies of familial Alzheimer’s disease in subjects with known presenilin mutations have found extensive Ab deposits in the frontal, temporal, parietal, and occipital neocortex, but fail to explicitly address the medial temporal lobe [102][103] [104].


Figure 13. Comparison of a Healthy Brain and a Brain Affected by AD (Figure Souce)

Animal Studies

Table 3.The following table was included in a review article written by Schaeffer, Figueiro, and Gattaz that describes common transgenic mouse models used to study AD pathogenesis. [12] From left to right, the table provides the name of the mouse model, genetic mutations induced, and resulting pathological features displayed. (Table Source)


Numerous studies using rats and mice have been conducted to examine the cellular mechanisms and processes involved in Alzheimer’s disease.

A study conducted by Um et al.[105] used transgenic mice Tg-NSE/hPS2m, which expressed the human PS2 mutation and compared them to control mice, who were labeled as non-Tg. Mice were sacrificed from each group and brains were removed and separated so the hippocampus and the extracted mitochondria could be analyzed using western blot analysis.[105] Tunel staining was also used to detect apoptosis.[105] It was found that phosphorylation levels of tau at the Ser404, Ser202, and Thr231 residues in the hippocampus in Tg mice were enhanced.[105] Increased phosphorylation levels of JNK1/2 and p38MAPK along with decreased levels of ERK1/2 phosphorylation were found in transgenic mice (Tg).[105] Tg mice also had higher levels of COX-2 proteins and higher levels of caspase-3 protein levels than control mice.[105] Cytochrome C and Bax protein levels were higher and lower levels of Bcl-2 protein were found.[105] Tg mice had lower NGF, BDNF, and p-CREB/t-CREB ratios.[105] Also SOD-1 ,SOD-2, and HSP-70 levels were lower in Tg mice.[105] Serum TC, insulin, and corticosterone levels were significantly increased in Tg mice.[105]

Another study conducted by Ke et al.[106] used APP/PS1 double mutant transgenic mice and compared them with wild-type mice. They specifically looked at the neuroinflammatory involvement in the brain of these transgenic mice. They found microglia activation was higher in the APP/PS1 Tg mice than wild-type.[106] BDNF levels were significantly lower as well.[106] Comparing adult and aged Tg mice, they found levels of various sertonergic neurons in the raphe nucleus significantly lower in aged mice than adult mice, along with decreased cholinergic neurons in the medium septum region and the horizontal diagonal band.[106]

Transgenic mice were also used by Parachikova et al.[50] to show increased gene expression levels in numerous inflammatory markers compared to aged matched control mice including pro-inflammatory IL1α and the IL1 receptor (IL1r2). The largest change in gene expression between Tg and non-Tg mice was in chemokine CXCL10 and increased mRNA levels for CXCL11 and the CCR3 chemokine receptor.[50] Cytokine receptors including for IL1 (IL1r2), IL10 (IL10rβ), and TNF (Tngrsf1a) were also increased in the brain all of which indicated an inflammatory response associated with and plaques.[50]

Nichol et al.[107] study also supports the inflammatory responses associated in the transgenic mice finding IL-1β and TNF-α to be significantly greater and protein levels of IFN-γ and MIP1α tended to be lower in the hippocampus of aged Tg mice compared to wild type mice. Another study conducted by Nichol and colleagues[108] used mice with APOE ε3 and ε4 genes to identify changes in the hippocampus associated between carriers of the apolipoprotein E (APOE) gene that is a known risk factor for AD. Hippocampal BDNF levels were similar between the ε3 and ε4 mice however ε4 mice had reduced tyrosine kinase B (Trk B) receptors by 50% which lead to compromised synaptic function and learning. [108]

One study looked more in depth at the protective effect of BDNF in rats against the neurotoxicity associated with accumulation which occurs in AD.[109] Cortical neurons were observed to identify the expression of mRNA levels finding that neurons had maximal levels of BDNF and TrkB.FL after 8 days in vitro and the TrkB.T1 receptor levels was weaker.[109] The cortical neurons were exposed to 1-42 and Aβ25-35 for 48 hours which induced a toxic effect with Aβ25-35 being more toxic.[109] BDNF was able to significantly protect cortical neurons from both 1-42 and Aβ25-35 with protections against Aβ25-35 being not complete at 80% and 1-42 toxicity being completely reversed.[109] NGF was also examined for a protective effect and had a weak effect on 1-42 and no effect on Aβ25-35 toxicity.[109] To investigate the involvement of Trk receptors in the protective effect of BDNF, cells were treated with K252a, a Trk receptor inhibitor 5 minutes before BDNF was added and K252a completely blocked the protective effect of BDNF on both 1-42 and Aβ25-35.[109] K252a added alone significantly decreased the cell survival.[109] Now building on the in vitro portion of this study, in vivo data was collected by injecting mice with Aβ25-35 (because of increased toxicity) into the IG or the 3rd ventricle.[109] Two groups were used with one group just injected with Aβ25-35 alone and another group with Aβ25-35 and BDNF.[109] Aβ25-35 injected alone did not modify changes in BDNF release however administration of BDNF, as done in group two strongly increased BDNF release, indicating BDNF administration increases BDNF release.[109] Further examination of the corpus callosum shows that animals receiving Aβ25-35 had a clear lesion consisting of myelin fragmentation which was attenuated in the BDNF-treated animals.[109] This indicates BDNF administration can prevent cortical neuronal loss that is associated with the cognitive impairment in AD.

Medical Management

AD is a debilitating illness in which the mechanisms accounting for its deleterious effects are still not fully understood. [110] Thus, medical management and treatment are still somewhat lacking. Recently, The Alzheimer’s Association has published guidelines outlining the medical management of AD. They state that exhaustive goals and plans encompassing all of the patient’s needs must be established before any treatment is implemented.[110] The assessment of the patient must consider all aspects of the patient’s care, such as: functional capacity, cognitive deficits, as well as, any other compounding comorbidities.[110]

Unfortunately, the FDA approved medications currently used with AD only treat the associated symptoms and not the disease process. [111] These symptomatic agents are know as acetycholinersterase inhibitors (AChEI) and moderate-affinity N-methyl-D-aspartate (NMDA) antagonist. [111] AChEIs increases the amount of acetylcholine circulating in the brain.[111] It is believed that cholinergic deficits are present in idividuals with AD. [111] A meta-analysis conducted through the Cochrane Database revealed the three main AChEIs: donepezil, rivastigmine, and galantamine to be effective treatments for individuals with mild to moderate AD. [112], [113] However, the researchers were still unable to gain any greater insight into why certain patients respond better to these agents when compared to their equivalents. [112], [113] The popular NMDA is known as Memantine and it is primarily being prescribed to those patients indentified as having moderate to servere AD. [112] Memantine is believed to be neuroprotective helping halt the damaging effects of excitotoxicity. [112] The research investigating the effects of Memantine on AD are far less extensive than those conducted on AChEIs. [112] However, a couple studies have proven Memantine to have positive effect on patients cognition and behavior in just 6 months. [114]

A lot of effort is being put towards identifying potential drugs that can actually alter the underlying mechanisms associated AD. [112] These agenets are being refered to as ‘disease-modifying’ drugs. [112]

Below is a summary of some agents currently being investigated:

Drugs interfering with Aβ deposition:

  • Anti-Amyloid Aggregation Agents – Tramiprosate is the leading candidate in this field. .[112] It mimics the sugar-protein compound known as glycosaminoglycan (GAG). .[112] GAGs bind to soluble Aβ and promote the formation of plaques. [112] By competing with GAG tramiprosate slows fibril formation and reduces soluble Aβ.[112]
  • Vaccination – Several studies are being implemented to determine if vaccination with Aβ as an antigen can help deter amyloid aggregation. [112] Studies have demonstrated that, as an antigen, Aβ promotes the removal of circulating amyloid from the CNS. In transgenic mice overexpressing the APP gene, vaccination with Aβ slowed the development of AD .[112] When given to young animals Aβ can prevent the occurance of AD pathologies related to Aβ.[112]
  • Selective Aβ42-lowering agents (SALAs) - Tarenflurbil is the current drug in this class being investigated for its ability to modulate γ-secretase activity. [112] Studies have demonstrated Tarenflurbil’s ability to bind with γ-secretase changings its make-up enough to shift its production away from Aβ42, while still allowing it to maintain the ability to perform other vital roles in the body. [112]
  • γ-secretase inhibiting agents – Current research has identified a multitude of different compounds that can prevent γ-secretase activity in the brain, [112] Unfortunately, experiments with transgenic mice have found that when these agents are given in sufficient doses to reduce Aβ amounts, that they also disrupt γ-secretase ability to differentiate lymphocytes. .[115], [112] Further studies are being conducted to assess the safety and efficacy of these agents going forward. [112]
  • α-secretase potentiating agents - Etazolate is the name of the drug in this class that is currently being investigated. [116],[112] Etazolate is believed to promote the non-amloidogenic pathway.[116], [112] In vitro studies, have concluded it to be neuroprotective against Aβ42, through its promotion of increased secretion of sAPPα.[112]
  • β-site APP cleaving enzyme (BACE) inhibition - Currently, the research into this class of drugs are in the very preliminary stages authors are still software programing to try to identify the compounds that best inhibit BACE.[112]

Drugs interfering with tau deposition:

  • tau-blocking agents - The compound referred to as methylthioninium chloride (MTC) is currently being researched in an effort to assess its effectiveness as a tau-blocking agent. [112] MTC is believed to prevent tau accumulation by acting on shortened tau fragments, which have been known to self-aggregate. [117] , [112] Along with MTC, further investigation is being conducted to see if tau deposition can be affected through the alteration of the kinases thought to play a role in the hyperphosporylation of tau. [112] Currently, the kinase known as glycogen synthase kinase 3 (GSK3β) has been identified as a prospective target for such treatments.[118], [112]


AD causes a wide range of cognitive impairments and eventually results in death.[9] Millions of Americans, primarily those aged 65 and older, suffer from the disease and this number is expected to continue to increase in the future.[1] As of 2010, AD was the sixth leading cause of death in the United States.[3] Despite extensive research, the exact cause of AD is not fully understood.[2] It is generally believed that the accumulation of plaques composed of the Aβ protein outside the cell and the accumulation of neurofibrillary tangles composed of tau protein inside the cell are key pathological features of the disease.[2] These features, along with mitochondrial dysfunction, synaptic failure, inflammation, lysosome dysfunction, and disruption of the adaptive cellular stress response pathways contribute to cell death, also known as apoptosis, in areas throughout the brain. Continued research on AD is necessary to gain a better understanding of the cellular mechanisms underlying the development of the disease and to create more effective treatment methods to halt or reverse disease progression.

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