1. Alzheimer's Disease Flashcards
what is the most common form of dementia
alzheimers disease
name 3 other types of dementia
vascular dementia
parkinsons dementia
frontotemporal dementia
who discovered AD
Alois Alzheimer
what was the name of Alois Alzheimer’s patient
Auguste D
what behaviours did Auguste D exhibit
changes in her behaviour: strong feelings of jealousy
memory impairment
speech and language difficulty
paranoia
what did pathological examination of Auguste D’s brain find
decreased brain volume
cortex was covered in localised deposits, and some neurons contained dense bundles of filament
name the 3 A’s for clinical symptoms of AD
agnosia
apraxia
and aphasia
what is agnosia
poor object recognition
what is apraxia
inability to make voluntary movements
what is aphasia
loss of speech and poor word recognition
what is the main symptom of AD
progressive loss of STM
what behavioural changes often accompany these physical symptoms
heightened aggression, agitation and sleep disturbances
what proportion of people aged over 80 does AD affect
1/6 people
what is the strongest risk factor for AD
age
is there a gender bias in AD
yes - prevalence and incidence is higher in women than men in Europe and Asia
what percentage of AD cases is due to genetic mutations
1.5% of total cases
what is the name given to AD when its due to genetic mutation, why?
familial AD - because these mutations occur within families
SNP at over how many genes is associated with an increased risk of developing AD
30 genes
which APOE genes is associated with sporadic AD
APOE2, APOE3, APOE4
why are APOE genes associated with sporadic AD and not familial AD
because these are polymorphisms at APOE and NOT mutations
if you have either 1 or 2 copies of APOE4 how many times more likely are you to develop AD at an early age
7-11 x more likely
what 3 modifiable factors predispose the individual to AD
metabolic and vascular factors
diet and nutrition
lifestyle
name 2 vascular factors that are risk factors for AD
diabetes
hypertension
what diet is associated with an increased risk of AD
high in saturated fats
low in vitamin B6 and B12
what can decrease the risk of developing AD
engaging in mentally stimulating activities or having a demanding job
name two histopathological features of AD
senile plaques (with a halo and a core)
neurofibrillary tangles
are senile plaques intracellular or extracellular
extracellular
are NFTs intracellular or extracellular
intracellular
where are activated microglia typically found in AD
aggregating around extracellular plaques
what other molecule (besides microglia) respond to cell damage
reactive astrocytes
what must be found for a pathological diagnosis
plaques AND tangles
(plaques are necessary but not sufficient)
what is the main component of senile plaques
beta-amyloid protein
what is the main component of NFT
tau protein
what stains identify beta-amyloid
congo red and thioflavin
where do dyes bind to beta-amyloid
on the beta sheets
what makes beta-amyloid resistant to proteolysis
they cannot be broken down due to strong beta-sheet structure
what is APP
a transmembrane protein ubiquitously expressed in neurons
what molecule cleaves APP into two fragments in the non-amyloidogenic pathway
alpha-secretase
in the non-amyloidogenic pathway, what two fragments is APP cleaved into?
soluble APP alpha
C83 (protein portion)
where does alpha-secretase cleave APP, what does this mean?
in the middle of the fragment
- this means that a full sequence of amyloid is not found in either APP fragment
what cleaves C83
gamma-secretase
gamma secretase cleaves C83 into
p3
what is p3
a small fragment less than 38 AA - it is not prone to any aggregation, it is excreted into the extracellular space and is removed by the brain
in the amyloidogenic pathway, what cleaves APP
beta-secretase
what does beta-secrete cleave APP into
soluble APP beta and C99
what is different about APP cleavage in the non-amyloidogenic pathway
it is not cleaved in the middle, so C99 contains the full-length fragment of beta-amyloid
what happens when gamma-secretase cleaves C99
a small fragment 40-42 AA in length is generated. this is called beta-amyloid 1-40/42
what is dangerous about beta-amyloid 1-40/42
it is prone to aggregation which results in the loss of neuronal function
what is the least toxic amyloid species
fibrils
what is the most toxic amyloid species
oligomers
AB40-24 are secreted as monomers, what makes them aggregate?
they have high kinetic energy
how long are amyloid fibrils
8-10 nm
how many APP mutations have been identified to date
50
what do PS1 and PS2 mutations relate to
the gamma secretase enzyme - these mutations give it greater cleavage properties
what are APP mutations hypothesised to do
leave the protein more likely to be cleaved by beta-secretase
what are neurofibrillary tangles composed of
two PHFs wound around each other
what are PHFs composed of
hyperphosphorylated tau
what happens when tau becomes hyperphosphorylated
it falls off the microtubule and aggregates together, destabilising the microtubule and neuronal communication = neuronal death.
how many isoforms does tau have
6
how are tau isoforms generated
via alternate splicing of mRNA
how many of the tau isoforms do PHFs contain
all 6 of them
what do MAPT mutations give rise to
frontotemporal dementia
NOT AD
what do pathogenic mutations do to tau
alter microtubule assembly or aggregation. properties
what is gliosis
the activation of microglia and astorcytes
what activates microglia and astrocytes
surveying microglia detect these abnormal protein deposits
microglia and astrocytes produce pro inflammatory cytokines, name 3 of them
1l-1beta
TNF-alpha
IL-6
what is the effect of these pro-inflammatory cytokines
they produce more neuronal damage = feed-forward mechanism as damaged neurons produce beta-amyloid and tau aggregates
what causes cerebral amyloid angiopathy
deposition of beta-amyloid in the walls of blood vessels (damages the BBB)
what evidence is there for the amyloid cascade hypothesis
animals that overexpress human APP mutations develop cognitive impairment and reduced spatial memory
treating animals with compounds that prevent or remove beta-amyloid show improvement in cognitive performance
what is the amyloid cascade hypothesis
aggregation of beta-amyloid sets off a series of downstream events, including inflammation, that results in the development of NFTs and cell death
what is the tau hyppthesis
proposes that tau pathology precedes beta-amyloid plaques and that NFTs are the main cause of neuronal death
what supporting evidence is there fore the tau hypothesis
animals that express human tau NFTs develop cognitive impairment and neuronal death
dementia is also observed in other tauopathies
treating animal models with compounds that prevent tau aggregation show improved cognitive performance
name another tauopathy characterised by dementia
progressive supranuclear palsy
what is the cholinergic hypothesis
acetylcholine is important for memory and attention - as cholinergic neurons die early in AD, preventing the catalysis of ACH could improve symptoms
name 2 drugs based on the cholinergic hypothesis
donepezil
galantamine
what is a nasty side effect of donepezil
vommiting
do PSYC317 questions for more info on AD drugs!!!!
yes do it bitch
how does memantine work
a non-competitive NMDA antagonist that competes with magnesium for binding int he channel - keeping it closed and preventing a calcium influx
how many AD clinical trials have failed
99.7%
name 3 types of drugs in the pipeline for AD treatment
immunotherapy - AB42 injections to stimulate an antibody response
beta-secretase inhibitors
gamma-secretase inhibitors
describe how immunotherapy is a tool for combatting AD
patients injected with pre-aggregated AB42 = antibodies
antibodies cross the BBB and attack senile plaques = disaggregation and phagocytosis
has immunotherapy been approved in the UK
no - only in the US (aducanumab)
what happened in the first trials of immunotherapy
they had to be stopped in phase 2 due to brain inflammation and death
what has prevented beta-secretase inhibitor development
they have been difficult to manufacture as a large binding site is needed for BBB penetration
what undesirable side effects are currently associated with beta-secretase inhibitors
worsening of cognitive decline
what was the problem with the first gamma-secretase inhibitors
they initially inhibited notch processing - which is important in the development of many cancers
why have these gamma secretase inhibitors been dropped
lack of potency, low brain penetration, poor selectivity, lack of efficacy
name 3 other approaches to treating AD
epigenetic - modify gene expression
inflammation - reduce gliosis
vascular - improve blood flow
what does memantine do
prevents overexposure to calcium and the production of free radicals which can cause cell death
