Alzheimer's disease pathophysiology
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Alzheimer disease (AD), is a progressive neurodegenerative disorder. The dysfunction of amyloid precursor protien (APP) metabolism and the resulting build up of of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals have been considered pivotal for neurodegeneration in the disease. Cognitive impairment in patients with AD is closely associated with synaptic loss in the neocortex and limbic system. In familial forms of AD, mutations result in an increased Aβ production or aggregation, in sporadic AD, failure of the clearance mechanisms might play a key role. Loss of mature neurons and alterations in neural progenitor cells (NPCs) in areas such as the dentate gyrus (DG) of the hippocampus have been found to be responsible for manifestations of AD. On gross pathology, temporal atrophy (hippocampus in particular), dilation of lateral ventricles and third ventricle are characteristic findings of Alzheimer's disease. The microscopic histopathological features of alzheimer's disease consist neurofibrillary tangles, senile plaques, neuronal loss, and with or without cerebral amyloid angiopathy.
Alzheimer disease (AD), is a progressive neurodegenerative disorder. The dysfunction of amyloid precursor protien (APP) metabolism and the resulting build up of of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals have been considered pivotal for neurodegeneration in the disease. There is also an accumulation of intracellular neurofibrillary tangles that consist of hyperphosphorylated tau protein and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus, and the neocortex.
The following factors lead to the development of Alzheimer's dementia:
(i) Neuronal loss
- Neurogenesis is a complex process characterized by several progressive steps, including neural progenitor cell (NPC) proliferation, migration, differentiation (cell fate commitment) and maturation, including growth and synapse formation
- Initial synaptic injury is followed by neuronal loss accompanied by astrogliosis and microglial cell proliferation.
- Cognitive impairment in patients with AD is closely associated with synaptic loss in the neocortex and limbic system
- Increase in neurogenesis in the brains of AD patients may be related to glial and vasculature-associated changes as suggested by an increase in neurogenic markers
- Loss of mature neurons and alterations in neural progenitor cells (NPCs) in areas such as the dentate gyrus (DG) of the hippocampus have been found to be responsible for manifestations of AD
(ii) Aggregation of extra-cellular amyloid β (Aβ)
- Amyloid precursor protein (APP) is physiologically present in normal brains
- It is proteolytically processed by α-, β-, and γ-secretases
- In familial forms of AD, mutations result in an increased Aβ production or aggregation, in sporadic AD, failure of the clearance mechanisms might play a key role
- Aβ oligomers are responsible for the synapto-toxic effects of Aβ
Constitutive (nonamyloidogenic) pathway
- In the constitutive pathway, proteolysis of APP by α- and γ-secretases results in nonpathogenic fragments (sAPPα and α-C-terminal fragment)
- In the amyloidogenic pathway, proteolysis of APP by β-secretase and γ-secretase gives rise to a mixture of Aβ peptides with different lengths. There are two major Aβ species: Aβ1–40 (90%) and Aβ1–42 (10%). The Aβ1–42 fragments are more aggregation-prone and are predominantly present in amyloid plaques in brains of AD patients.
- Abnormal accumulation of Aβ is the result of an imbalance between the levels of Aβ production, aggregation and clearance.
- Aβ clearance is mediated by proteolytic enzymes such as neprilysin, chaperone molecules such as apoE, lysosomal (e.g. autophagy) and non-lysosomal pathways (e.g. proteasome)
- Nerve damage as described under 'neuronal loss', might result from the conversion of normally non-toxic monomers to toxic oligomers of Aβ peptides
- Changes in glutamate receptors and increased excitability; mitochondrial dysfunction; lysosomal failure and alterations in signaling pathways related to synaptic plasticity, neuronal cell death and neurogenesis have been proposed as the molecular mechanisms leading to the development of Alzeimer's dementia (AD)
(iii) CDK5 pathway
- CDK5 is the predominant CDK found in the brain, is expressed heavily in neurons and plays a key part in synaptic integrity and neuronal development
- Increased activation of CDK5/p35/p25 has been linked to the pathogenesis of neurodegenerative diseases such as AD
- CDK5 may mediate changes in neurogenesis in AD via aberrant phosphorylation of CDK5 substrates, which include cytoskeletal (neurofilaments, nestin), synaptic proteins (synapsin)
(iv) Formation of intraneuronal neurofibrillary tangles (tau protein accumulation)
- Aβ is involved in tau deposition in AD pathogenesis and leads to the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau increases Aβ toxicity via a positive feedback loop
- A protein that functionally links Aβ to tau is fyn. This cytosolic tyrosine kinase positively regulates N-methyl-D-aspartate (NMDA) receptor activity and has been shown to be targeted to postsynaptic sites in dendrites by tau, which binds fyn
- In response to Aβ, tau is relocated from axons and dendrites into the somatodendritic compartment
- Excess fyn accompanies the excess tau in AD dendrites and upregulates NMDA receptor activity in those areas, causing an increased calcium influx. This calcium-driven excitotoxicity can damage postsynaptic sites and cause neurodegeneration
GeneticsGenetic origin of Alzheimer's dementia (AD) demonstrates an autosomal dominant pattern of inheritance. Alzheimer's dementia arising from genetic alterations may lead to early onset (<60 years) of disease. The following mutations are implicated in the development of AD are:
Early onset (Alzheimer's dementia-AD 1, 3 and 4)
- Presenilin1 (PS1) gene, also called PSEN1 gene on chromosome 14 (AD3- 20 to 30 percent cases)
- Presenilin 2 (PS2) gene, also called PSEN2 gene on chromosome 1 (AD4- rare)
- Point mutations in amyloid beta A4 protein gene, also called amyloid precursor protein (APP) gene on chromosome 21 are associated in some cases of early onset (< 65 yr) familial AD cases
Late onset (Alzheimer's dementia -AD2)
- Apolipoprotein 4 gene (APOE4) mutation is associated with late onset (>60 years) Alzheimer's dementia (AD)
- p.Arg47His allelic variant in TREM2 gene
Less common genes
Less common genes associated with the development of AD are:
- A2M on chromosome 12
- ABCA7; when suppressed, results in an elevation of amyloid production
- AKAP9, a kinase anchor protein 9 (PRKA) that regulates NMDA channel activity
- There is evidence both for and against ADAM10
- BIN1, a tumor suppressor protein
- CALHM1 on chromosome 10q24; CALHM1 influences calcium homeostchaperon has a single nucleotide polymorphism (SNP) associated with late-onset AD
- CD2AP, an adaptor molecule involved in dynamic actin remodeling and membrane trafficking
- A SNP in CD33
- Clusterin (CLU, APOJ), a molecular chaperon present in senile plaques that has CR1 and PICALM, implicated in two genome-wide association studies (GWAS)
- Dysferlin (encoded by DYSF), associated with several limb-girdle muscular dystrophies; accumulates in Alzheimer patients
- EPHA1 (encoding a protein that belongs to the ephrin receptor subfamily); plays part in synaptic plasticity
- GAB2 on chromosome 11q14 interacting with the APOE e4 allele
- GST01 and GST02 on chromosome 10
- PAX1P1, which encodes for a nuclear protein that may function in DNA repair pathways
- PLD3 on chromosome 19q13.2
- SORL1 on chromosome 11q23, a protein involved with APP protein trafficking
- TOMM40, located on chromosome 19q very close to the APOE locus,TOMM40 has been implicated in late-onset AD both by linkage analysis and by the presence of a variable length poly-T repeat within the gene
- UNC5C is enriched in neurons of the hippocampal pyramidal layer
- In a large GWAS meta-analysis, the following genes have been identified as rare causes of Alzheimer's disease:
- Several other potential loci under investigation on the following chromosomes:
- On gross pathology, temporal atrophy (hippocampus in particular), dilation of lateral ventricles and third ventricle are characteristic findings of Alzheimer's disease.
- The microscopic histopathological features of alzheimer's disease represent neurofibrillary tangles, senile plaques, neuronal loss, and with or without cerebral amyloid angiopathy:
- Neurofibrillary tangles: Consists of tau, location in the hippocampus, cerebral cortex, hypothalamus. Dementia severity correlates better with neurofibrillary tangles number rather than senile plaque number
- Senile plaques or the neuritic plaques consists of two components which are A-beta amyloid which radiate from the center and the neurites with swollen axons. Senile plaques are considered to be more specific for alzheimer's than neurofibrillary tangles
- Loss of neurons
- With or without cerebral amyloid angiopathy
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