Lecture 44 - Alzheimer's Disease and Other Dementias - Pathophysiology and Pharmacology Flashcards
Alzheimer’s disease (AD) is
an age-related neurodegenerative disorder
Survival following diagnosis: 3 – 20 years (mean = 8 years)
2:1 female:male (opp of PD)
AD is the major cause of
dementia
AD symptoms
(1) memory loss (especially recent memories)
(2) impaired ability to learn, reason
(3) impaired ability to carry out daily activities; confusion, untidiness
(4) anxiety, suspicion, hallucinations
(5) motor dysfunction can also occur in late-
stage disease
Environmental risk factors of AD
- Age (major risk factor)
- Low educational level
- Reduced mental activity in late life
- Reduced physical activity in late life
- Risks for vascular disease
- Head injury
AD neuropathology:
loss of brain volume
amyloid plaques and neurofibrillary tangles
synapse loss
Amloid plaques
- extracellular
- consist of amyloid-β peptide (Aβ)
Neurofibrillary tangles
- intracellular
- consist of hyperphosphorylated tau
Progression of AD neuropathology
largely in basal forebrain and nucleus basalis and entorhinal cortex
- AD neuropathology (plaques and tangles spreads through the cortex as the disease progresses.
- Neuropathology primarily affects areas of higher cognitive function:
→ entorhinal cortex (memory formation/consolidation)
→ hippocampus (memory formation/consolidation)
→ basal forebrain cholinergic systems (learning)
→ neocortex (memory, learning, cognition)
→ nucleus basalis (memory, attention, arousal, perception)
Synapse loss
- A striking feature of neurons with neurofibrillary tangles and neurons in the vicinity of amyloid plaques is the destruction of synapses.
- Synapse loss results in reduced levels of neurotransmitters – especially acetylcholine, but also serotonin, norepinephrine, and dopamine.
- Another consequence: dysregulated glutamate –> excess excitotoxicity and neurotoxicity
Which is the key pathogenic molecule: Aβ or tau?
- Genetic evidence suggests a key role for Aβ :
→ Mutations in the gene encoding the Aβ precursor protein, APP, are linked to early onset AD.
→ Trisomy 21 (Down’s syndrome) is associated with an AD-like phenotype in the 4th decade of life, and the APP gene is located on chromosome 21.
→ Mutations in the gene encoding presenilin proteins involved in cleaving Aβ from APP are linked to early onset AD.
Production of Aβ peptide from APP
- Aβ peptide is released from the transmembrane amyloid precursor protein (APP) by the activity of β-secretase (BACE1) and γ-secretase.
- Cleavage of APP by α-secretase in the middle of the Aβ segment releases a non-amyloidogenic (non-toxic) fragment.
- Aβ is generally 40 or 42 amino acid residues in length. Aβ42 forms amyloid fibrils more readily than Aβ40.
- Mutations in the APP gene favor cleavage by β- or γ-secretase, resulting in the production of more Aβ42 relative to Aβ40.
- Mutations in the gene encoding presenilin-1 or presenilin-2 (PSEN1 or
PSEN2), which are components of the γ-secretase complex, alter APP cleavage by γ-secretase, resulting in the production of more Aβ42 compared to Aβ40.
Effects of Aβ aggregation on tau pathology
- Aβ aggregation is thought to promote tau hyperphosphorylation, leading to neurofibrillary tangle formation, cytoskeletal anomalies, and disruption of axonal trafficking.
early aggregates can bind to cell surface receptors linked to kinases in cell –> kinase activation –> tau hyperphosphorylation –> neurofibrillary tangles –> disruption of cytoskeleton, axonal trafficking
Neurofibrillary tangle formation results in
cytoskeletal defects
In healthy areas the microtubule tracks are well organized and thus permit the trafficking of cargoes (e.g. vesicles, organelles) down the axon. This transport is critical for proper synaptic function.
In unhealthy areas where tangles have accumulated, the cytoskeletal tracks are disrupted and disorganized, resulting in defects in axonal transport that lead to synaptic dysfunction.
becomes disrupted when tau becomes hyperphosphoylated
Effects of Aβ aggregation on microglial activation
- In addition to causing damage to neurons directly, Aβ is thought to induce neurotoxicity indirectly by triggering microglial activation, a process that is probably aimed at clearing amyloid from the brain.
- Activated microglia release pro-inflammatory cytokines (e.g. prostaglandins, interleukins, tumor necrosis factor-α) that cause neuroinflammation.
- Activated microglia also release reactive nitrogen species (e.g. nitric oxide, peroxynitrite) and reactive oxygen species (superoxide, hydrogen peroxide) that cause oxidative stress.
Impact of ApoE genetics on AD risk
– ApoE – responsible for transporting cholesterol in brain (LDL); altered ApoE function can affect Aβ aggregation or clearance.
– ApoE genetics:
→ There are three ApoE isoforms as a result of polymorphisms
in the ApoE gene: ApoE2, ApoE3, and ApoE4.
→ Individuals with one or two ApoE4 alleles have an increased
risk of AD, whereas inheritance of the ApoE2 (protective) allele decreases AD risk.
