8. Alzheimer's Flashcards
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
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
What are the research steps in drug discovery for diseases such as AD?
What are the steps of clinical trials in developing drugs for diseases such as AD?
Have there been any drugs developed for AD?
No, lots of attempts but non effective - complex disease, hard to target
What are currently most successful approaches for AD treatment?
In development - immunotherapies against
- amyloid: beta secretase, gamma secretase inhibitors, alpha secretase activators - don’t work
- Tau: stop phosphorylation - moderately ok
