Alzheimer's Disease Flashcards
What are the characterisations of AD?
Progressive loss of short-term memory
Aphasia - loss of speech, poor word recognition
Apraxia - inability to make voluntary movements
Agnosia - poor object recognition
(often also heightened aggression, agitation, sleep distrubances)
What are some non-modifiable risk factors for AD?
Age
= 1/6 over 80
Sex
= higher in women
Genetics (familial AD)
= mutations (mostly sporadic) in genes coding for:
APP (amyloid precursor protein)
PS1 (presenilin 1)
PS2 (presenilin 2)
What are some modifiable risk factors for AD?
Metabolic / Vascular Factors
= diabetes, hypercholesterolaemia, obesity
Diet / Nutrition
= high saturated fats , low folic acid, vitamins B6 / B12
Lifestyle
= smoking, alcohol, physically inactive
= socially active, mental stimulation can help
Summarise the main pathology in AD?
β-amyloid plaques (extracellular)
Neurofibrillary tau tangles (intracellular)
= also:
reactive astrocytes
activated microglia
synaptic dysfunction + neuronal death = brain shrinkage
What is β-amyloid
= makes up extracellular senile plaques
= caused by protein misfolding
= found in many diseases in many tissues / organs
= made from approx. 30 different proteins
= identified by congo red / thioflavin stains
= 8-10 nm beta-sheet fibrils
= resistant to proteolysis
= has two major forms:
Aβ40
Aβ42
= spontaneously aggregate in vitro into amyloid fibrils (Aβ42 - more quickly)
What are the 2 pathways for processing amyloid precursor protein (APP)?
Non-amyloidogenic pathway
Amyloidogenic Pathway
How does the non-amyloidogenic pathway for APP processing work?
APP
enzyme = α-secretase
= sAPPα (soluble)
+
= C83
enzyme = γ-secretase
= p3 = <38 a.a
= NO AGGREGATION
How does the amyloidogenic pathway for APP processing work?
APP
enzyme = β-secretase
= sAPPβ (soluble)
+
= C99
enzyme = γ-secretase
= Aβ = 40-42 a.a.
= AGGREGATION
What is the toxic oligomer hypothesis?
Process:
Monomers - Oligomers - Protofibrils - Amyloid fibrils
(can jump steps)
(can go both ways)
= oligomers may be the most toxic form of Aβ
Name some key APP mutations?
They are named after the countries they were discovered in:
London mutations
Iowa mutaion
Flemish mutation
Swedish double mutation
(over 50 identified)
What are neurofibrillary tangles (NFTs)?
process:
microtubule - tau hyper-phosphorylation - paired helical and straight filaments - tau neurofibrillary tangles
= NFTs made from paired helical filaments (two 10-20 nm filaments wound round each other - cross-over at every 65-80 nm)
= paired helical filaments (PHFs) arise from hyperphosphorylation of microtubule-associated protein TAU (MAPT)
= MAPT involved in axonal microtubule assembly and stability
What about Tau isoforms?
There are 6 main isoforms of tau
= derived by alternative mRNA splicing from single MAPT gene on chromosome 17
(1 of which is foetal tau)
What happens in Tau phosphorylation?
PHFs (paired helical filaments)
= contain all 6 tau isoforms
= tau in PHF is highly phosphorylation (hyper) at multiple Ser-Pro, Thr-Pro site
BUT role of phosphorylation in NFT formation is unclear
Foetal brain = 20% tau phosphorylated
Normal adult brain = <5% tau phosphorylation
PHFs = 100% tau
What are MAPT (microtubule-associated protein tau) mutations?
= give rise to frontotemporal dementia (not AD)
= all 6 tau isoforms affected by mutation in:
exon 9, exon 12, exon 13
= only affect tau isoforms with four microtubule-binding repeats
exon 10
= pathogenic mutations alter tau production + lead changes in microtubule assembly or aggregation properties
Chronic inflammation in AD?
= a feed forward cycle
Aβ + Tau = cause injury = astrocyte and microglial activation
= increased proinflammatory elements
(e.g. IL-1β, IL-6, TNF-α)
= neuronal damage / death
Vascular damage in AD?
Cerebral amyloid angiopathy
= deposition of Aβ in walls of brain blood vessels
Damage to BBB
Dysregulated cerebral blood flow
Changes in cerebral perfusion may be one of earliest features in AD?
What are 3 of the hypotheses for AD?
Amyloid Cascade Hypothesis
Tau hypothesis
Cholinergic hypothesis
(EXTRA READING - MORE HYPOTHESES?)
= also INFLAMMATION hypothesis
(chronic inflammation - damage neurons and leads to accumulation of amyloid and tau)
= also OXIDATIVE STRESS hypothesis
(imbalance between production of ROS and detoxifying of them = accumulation leads to neuron damage)
= also VASCULAR hypothesis
(due to reduced blood supply , leaky blood vessels = reduced oxygen + nutrients to neurons)
What is the Amyloid Cascade Hypothesis? (+evidence)
= aggreagation of Aβ sets of series of downstream events (synaptic dysfunction, inflammation)
= leads to development of PHFs, NFTs = cell death
Evidence:
= strong association between mutations in genes that increase Aβ production + risk of AD
= treatment with Aβ causes death of neurons
= Aβ can induce tau phosphorylation in vitro
= animals that overexpress human APP mutations develop cognitive impairment (decreased spatial memory)
= treatment of animal models with compounds that prevent Aβ accumulation / remove aggregated Aβ = improve cognitive performance
(EXTRA READING - MORE EVIDENCE)
= genetic mutations in PS1/2 identified as familial AD cause
= imaging studies - can visualise amyloid deposition
What is the Tau Hypothesis? (+evidence)
= that tau pathology precedes Aβ PLAQUES
= that NFTs are main cause of neuronal dysfunction and death
Evidence:
= animals that express human tau NFTs develop cognitive impairment + neuronal death
= treatment of animal models with compounds that prevent tau aggregation show improved cognitive performance
= pathological studies have reported tau lesions earlier than Aβ accumulation in human brains
= Braak staging of tau pathology strongly correlated with extent of cognitive + clinical symptoms
= dementia observed in other neurodegenerative diseases where NFTs are present
What is the Cholinergic hypothesis?
(EXTRA READING)
= that detrioration of cholinergic neurons is significant factor in development of AD
= acetycholine is important for memory + attention
= cholinergic neurons die early in AD
(treatment - keep Ach in synapse for longer = improved memory)
What are the some current treatments for AD?
AChE inhibitors
= donepezil, rivastigmine, glantamine
NMDA (glutamate) uncompetitive antagonist
= Memantine = competes with Mg2+ for channel binding
Combination regiments
= memantine + donepezil
= currently approved treatments are symptomatic
EXTRA READING
What are the key drug targets?
Prevent Aβ formation
Prevent, reverse or remove Aβ aggregation
Prevent or remove PHF and NFTs
How does immunotherapy (vaccination) work?
= Injection of pre-aggregated Aβ42 into blood-stream causes development of antibodies to fibrillar Aβ
= Antibodies cross BBB , attack senile plaques
(removed by Fc-receptor mediated phagocytosis, disaggregation of Aβ + drainage of soluble Aβ into plasma)
= Antibodies may also block Aβ fibrillation and toxicity
BUT trials stopped due to brain inflammation / death
= passive immunisation trials still going (monoclonal antibodies) - none succeeded
How do β-secretase inhibitors work?
= development difficult due to large binding site and need for BBB penetration
= e.g. Lanabecestat, Verubecestat - recently dropped due to lack of efficacy
= worsening of cognitive decline / other side-effects due to interference with BACE progressing of numerous substrates
(involved in ion channel formation, synaptic maintenance, axon guidance, myelination)
(β-secretase = 1st enzyme in amyloidogenic pathway = aggregation of Aβ)
How do γ-secretase inhibitors work?
= these inhibitors initially inhibited Notch processing (dysregulated in many cancers) = side-effects
= later ‘notch sparing’ γ-secretase inhibitors
= γ-secretase critical in processing of other type I membrane proteins
(e.g. ErbB4, E-cadherin, N-cadherin, ephrin-B2 , CD44)
= inhibitors dropped due to lack of potency, low brain penetration, poor selectivity, side-effects, lack of efficacy
(β-secretase = 2nd enzyme in amyloidogenic pathway = aggregation of Aβ)
What are some other approaches to treatment options?
Metabolism
= repurpose diabetes drugs (e.g. metformin)
Inflammation
= reduce gliosis
Vascular
= improve blood flow
Neurogenesis
= strengthen synapses or regrow neurons
Epigenetics
= modify gene expression
