AD Flashcards
what is dementia ?
progressive loss of cognitive and intellectual functions without impairment of perception or consciousness
what are the causes of dementia?
caused by a afriety of disorders including severe infections and toxins but most commonly associated with structural brain disease
what is dementia characterised by?
- disorientation
- impaired memory
- judgement
- intellect
what are the range of disease in dementia and that could act as cause?
- Alzheimers disease
- Vascular dementia
- mixed - AD + VD
- dementia with levy bodies
- parkinsons dementia
- fronto-temporal dementia (FTD)
what are the macroscopic neuropathological hallmarks of AD?
- cortex atrophy, hippocampus atrophy by 4-8% a year
- deeper and wider sulci
- smaller gyri
which region is not affected in AD?
- cerebellum not affected in AD therefore used as controls in some studies
what are the microscopic neuropathological hallmarks of AD?
plaque = amyloidpathy, extracellular tangles = tauopathy, intracellular
what is the break staging?
neurofibrillary tangles had characteristic distribution pattern in six stages
Stage 1 and 2 – trans entorhinal, clinically silent
Stage 3 and 4 ) – limbic, in developing AD
Stage 5 and 6 – neocortical, fully developed AD
what is CAA?
cerebro amyloid antipathy
- cerebral hypoperfusion due to accumulation ot tau around affected arteriole
- demonstrated several years before the onset of clinical AD
what are proteinopathies seen in brain disease?
- Lewy bodies (alpha syncuclein) - PD, LBD
- TDP43 inclusions - ALS, FTD
- FUS - ALS, FTD
- Tau protein - AD, FTD, CBD
what are the misfolded proteins in AD?
- beta amyloid
- hyperphosphorylated tau
- alpha-synuclein
- TDP-43
what are the three main mutations that were found in early onset Alzheimers (EOAD)?
- Amyloid precursor protein - APP ~50mutations
- Presenilin 1 ~220 mutations
- Presenilin 2 ~15 mutations
the mutation of the early onset Alzheirmer’s (EAOD) is mainly
- Familial AD (FAD)
- sporadic AD (SAD)
- Familial AD (FAD)
on which chromosome is APP gene found?
chromosome 21, 18 axons in man and is highly conserved
what is the structure of APP?
- transmembrane protein with large extracellular domain
- consists of a N and C terminal with alpha, beta and gamma site on the Abeta domain
how many isoforms are present in APP and how long is the shortest one?
8 isoforms
shortest one - 695AA (highly expressed in brain)
APP is not just expressed in brain but is concentrated at synapses also?
A. True
B. False
A. True
what and how are the two products obtained from APP processing?
- soluble APPalpha - the proteolytic activity (cutting by proteases) at the alpha site results in soluble APPalpha
- soluble abeta - the proteolytic activity at beta and gamma cleavage site results in soluble abeta
what is the function of
- soluble APPalpha
- soluble abeta
- soluble APPalpha - mediates neuronal growth
- soluble abeta (1-40,1-42) - when liberated they stick to each other forming aggregates and plaques which result in neuronal loss
where are they most likely to play a role?
- abeta1-40
- abeta1-42
- abeta1-40 in CAA (cerebro amyloid angiopathy)
2. abeta1-42 in brain parenchyma
which enzyme mediates the proleptic activity at the gamma cleavage site?
gamma secretase
why do APP mutations cause AD?
~50 mutations in ~120 families and almost all dominant
what type of proteases are PSEN1 and 2?
aspartyl proteases
how many components are present in gamma secretase and which is they key one?
- 4 components
- key one = presenilin 1, forms the catalytic of subunit go gamma secretase
what are the following features of PSEN1?
- chromosome
- axons
- mutations
- chromosome 14q
- 12 axons
- 220 mutations - the most common form in FAD >50% cases
what is the role of GWAS?
to identify SNPs and other variants in DNA associated with a disease but cannot specify casual genes on their own
what is tauopathy composed of and it forms into what?
composed of hyperphosprylated tau protein which forms into paired helical filaments
what is the structure of tau?
- on which chromosome
- axons
- isoforms
- tau protein located on chromosome 17q of MAPT gene in humans
- 11 axons and 6 isoforms
what does the hyperphosphorylation of tau result in?
- self assembly to PHFs/SF (paired helical filament/ straight filament)
- sequestration of normal tau, MAP1 and MAP2 and consequent disruption of MTs
what is the number of moles of phosphate per mole of tau in healthy and AD individuals?
healthy individual - 2-3 moles of phosphate per mole of tau
AD - this rises to to 3-4 fold
how does tau protein mediate self assembly?
some tau protein in AD brain becomes truncated which seems to promote self assembly
where is tau mislocalised in AD?
usually found in axons but in AD they translocate to different places like spine
what is the prionic spread of tau?
it is the idea that tau is transmitted b/w neurons, thus supporting the ‘neuronal connectivity’ account of pathology spreading
how do we know that tau has prionic spread?
inoculation of tau aggregates isolated from the AD patients brain/ tau transgenic mice/ other tauopathies into human tau transgenic mice or WT type mice induces time-dependent spread of tau pathology from the inoculation site to synoptically connected brain regions
how to stop AD?
- stop APP from being turned into abtea fragments/ stop the abeta formation from APP
- destroy the abeta fragments
- stop the abtea from assembling into toxic forms (stop the plaque formation)
- understand how abeta causes trouble (neuronal toxicity) and then intervene
- stop tau pathology (+ kinase block - to prevent the phosphorylation)
- stop the prionic spread of tau
how does one show new drugs work?
- memory tests - ADAS-Cog, MMSE
2. brain imaging - MRI, PET
how are the animal models of dementia created?
- genetically modify mice to produce dementia like pathology in the brain
- by introducing mutations that produce inherited human dementia into mice
- e.g. APP knock in mice for AD
what are the ways to measure mouse memory?
- Morris water maze test
- PDAPP mouse
- imaging single mouse neurons working in the intact brain
- testing drugs
what is the difference between beta and gamma secretase?
- beta secretase enzyme is BACE1 and gamma secretase consists of PSEN, PEN2
- beta secretase cleaves the APP protein at N terminal (~1) and gamma secretase cleaves at C terminal (~40)
