8. Alzheimer's Flashcards
(29 cards)
How are dementia and Alzheimer’s related?
Dementia - refers to a group of symptoms that affect memory, thinking, problem-solving, and communication skills - interfere with daily life - a group of neurological conditions - failure of higher neurological function
Alzheimer’s disease (AD) can cause dementia, AD a type of dementia
How are higher neurological functions examined?
Higher neurological functions examined by:
- orientation
- short-term memory
- clock-drawing test
- executive function
- language abilities
- animal naming
- abstraction
- attention
What are the different human neurodegenerative disorders?
Main two classes:
- dementia
- movement disorder
What diseases are caused by abnormal proteins?
Some neurodegenerative diseases manifest from accummulation of abnormal proteins - toxic gains for function (ex. protein accumulation in absence of autophagy for cellular maintenance)
How are abnormal protrins formed in neurodegenerative diseases?
Abnormal proteins come from:
- abnormal protein cleavage
- protein misfolding
Why in disease large quanities of abnormal protein are not cleared?
Abnormal proteins are produced in large quantities - organism noticed that they are wrong - marks fro degradation with Ub - to be degraded in proteosome - but proteosome can’t - because of aggregation / too unfamiliar structures (too many beta sheets) - mechanism gets overwhelmed => abnormal proteins don’t degrade, accummulate
What are the stats of Alzheimer’s?
Alzheimer’s:
- the most common cause of dementia in UK
- 99% cases are sporadic Alzheimer’s
- <1% are familial - have genes that definitely induce AD
- increased incidence in Down’s syndrome - because genes causing AD are on chrm21 - trisomy 21 increase quantitites of abnormal protein
- no definite diagnostic tools - only PET scans
- most prevalent in older age
- females affected more than males
What are the structural brain differences induced by Alzheimer’s?
Alzheimer’s induces ceberal atrophy - bigger ventricles, atrophic tissue -> loss of brain tissue in AD
What are the two proteins involved in Alzheimer’s?
- beta amyloid
-
Tau
accumulation in brain tissue - forms plaques
Explain beta amyloid pathology
Amyloid - transmembrane protein - encoded by** APP gene** - mutations in APP gene - leads to different processing:
- non-amyloidogenic - alpha secretase - cuts in beta amyloid fragment -> no beta amyloid produced
- amyloidogenic - beta secretase - cut away from beta amyloid fragment -> beta amyloid produced
Explain the two pathways of APP protein processing
- non-amyloidogenic - alpha secretase - cuts in beta amyloid fragment -> no beta amyloid produced
- amyloidogenic - beta secretase - cut away from beta amyloid fragment -> beta amyloid produced
Explain how APP protein processing occurs in the membrane
Explain how amyloid protein accumulates in vessels
Beta amyloid production from beta secretase pathway of APP processing - beta amyloid accumulation in the brain - transported into blood vessels - systems in Alzheimer’s overwhelmed - can’t remove beta amyloid effectively => impaired beta amyloid clearance - build up around capillaries -> AD
Noticed: in brain injuries often beta amyloid accumulates - but then cleared up - in AD can’t clear up
What can be used to image amyloid build up in the brain?
PET scans - can image amyloid and Tau protein accumulation in the brain - visible in mild cognitive impairment -> later progression to AD
Explain the pathology of Tau in AD
Tau protein encoded by MAPT gene (microtubule associated protein Tau) - mutations in MAPT don’t cause Alzheimer’s alone APP must act together - MAPT has different isoforms with different functions:
- microtubule stabilization
- microtubule spacing
- cellular signalling
- axonal transport
- protein fibrilization
What causes abnormal Tau function?
Abnormal Tau function caused by abnormal phosphorylation - Tau stabilizes microtubules but when abnormally phosphorylated - doesn’t function and microtubules start to fall apart + accumulation of highly phsophorylated Tau starts to kill off neurons - neurofibrillary tangles
Tau PET scan
What is the molecular pathology of AD?
- beta amyloid deposition
-
Tau hyperphosphorylation
-> widespread activation of microglial cells and** release of cytokines** (but not actual inflammation, not like MS)
What are the genetics of AD?
Genetics plays a role:
Familial AD:
- amyloid precursor protein (APP)
- presenilin 1 (PS1) - most common AD mutation
- presenelin 2 (PS2)
Sporadic AD:
- apolipoprotein E
- 99% of cases
Which is more common, familial or sporadic AD?
Sporadic AD 99%, familial very rare, but more aggressive - mutations in APP, PS1, PS2
Why are mutations in presenilins 1 and 2 cause AD?
PS1 and PS2 - essential for gamma secretase cleavage of APP - function as catalytic subunits for gamma secretase
distributed throughout the coding sequence
How does apopilpoprotein E affect AD development?
Apopilpoprotein E (ApoE) causes sporadic AD - its genotype afffects age of onset in both sporadic and familial:
-epsilon4epsilon4 - early onset
- epsilon3epsilon2 - protective function against AD
ApoE present in beta amyloid plaques, may interact with Tau neurofibrillary tangles
What are the risk factors for AD?
Risk factors divided into groups:
- cannot be changed to decrease AD risk
- can be changed to decrease AD risk
Regulatory network of AD development
