Lecture 9 Flashcards
(33 cards)
How high is the incidence of dementia in the USA?
At 65, 11% of people have dementia, and 70% of them had Alzheimers, and by 85, 47% of people have dementia
How common is early onsent Alzheimers?
in 5-10% of Alzheimer’s cases
How long does it take between mild cognitive impairment to diagnosis?
~5 years
What is neuroanatomy of Alzheimers?
Cortex was reduced, ventricles are larger and the brain is drawn away from the skull
What are the Alzheimer’s symptoms?
- Forgetfulness
- Untidiness
- Confusion
- Less movement
- Storage of new memory reduced
- Finally loss of bodily function
How can Alzheimer’s be images using a PET scan?
Can monitor energy metabolism in the brain and see that Alzheimer.s patient loses majority of their energy metabolism (e.g. at hippocampus)
What are the cellular features of an Alzheimer’s brain?
Plaques of ß-amyloid and tangles of tau
What are the three genetic hypothesis?
Tau, ß-amyloid and APOE
What is tau required for?
Microtubule integrity, and must move to let cargo past
How is binding of tau to microtubules usually controlled?
Phosphorylation
tau-p is unbound and tau is bound
What effect do tau-p mutations have?
Mutants of tau that are more readily phosphorylated cause neurodegeneration
What kinases phosphorylate tau?
- GSK3
- CDK5
- MARK
Why is tau-p hypothesised to cause neurodegeneration?
Allows for formation of tangles
Which disorder caused a higher incidence of Alzheimer’s?
What hypothesis did this lead to?
Down Syndrome
Cloning of chromosome 21 (focus due to trisomy 21) showed detrimental mutations in βAPP (amyloid precursor protein); Amyloid hypothesis
One mutation was actually beneficial in stopping Alzheimer’s; A673T
Mutations in what gene are seen in early onset familial AD?
What effect do the mutations have?
Presenilin I and II
Lead to increased Aβ production as code for secretases β and γ that cleave βAPP
What other secretase is involved in processing of βAPP?
What is its role?
α secretase - forms sAPPα, a neuroprotective form of Aβ
What was shown about β secretase in AD using mice models?
β secretase knockout mice rescue mouse model of AD; so β secretase important for AD development
What is produced by β and γ secretases?
β releases sAPPβ. Cleavage by γ on the propeptide remaining after β action forms Aβ oligomeres. Which the form plaques
How does the Aβ spread?
Released into extracellular space and taken up by other cells which then show damages endosomes
What issues have arisen about the pathway to Aβ production?
The Presenilin genes products are actually found on the endosome and golgi membranes not the cell membrane; so whole story has not yet been uncovered.
In familial AD what causes the plaques?
Not over production of Aβ but an inability to degrade it
Which enzymes are important for degradation of Aβ?
Neprilysin
Knockout mice have more Aβ
How might Aβ affect the synapses?
Able to ‘stick’ to lots of other proteins and affect synaptic transmission
How is Aβ linked to tau?
Aβ impairs MT transport
Some evidence of them forming complexes together
Aβ oligomeres induce mis-sorting of tau
