Flashcards in L9 - Alzeimer's Deck (37):
What are the symptoms of Alzheimer's?
Loss of bodily function
What is the neuroanatomy of an Alzheimer's patient?
Layers of neurons get thinner, big gaps in cortex
What did PET scans of someone going through Alzheimer's show?
Loss of energy metabolism around brain
What are the cellular changes in Alzheimer's?
Beta- Amyloid plaques
Where does tau build up?
what does tau normally do?
Helps stabilise microtubules and axon transport
What can indirectly cause hyperphosphorylisation of tau?
What direct events can cause the hyper-phos of tau
Upregulating of tau kinases
Downreg of phosphatases
What does the LOF of tau cause?
Detachment of MT
What can the GOF of tau cause?
NFTs made of hyperphosphorylated tau sequester normal tau.
NFTs become physical obstacles of vesicles
How does tau normally function?
Gets in the way of cargo but is required for MT integrity
Usually dephosphorylated to move out the way for motor proteins
What do tau-P mutations cause?
More readily phosphorylated and lead to neurodegeneration
What first suggests the amyloid hypothesis exists?
Down's syndrome leads to AD by 40, linked to chr 21
What other proteins could affect tau phosphorylation?
GSK3, CDK5 AND MARK
What happened when amyloid-Beta was synthesised and put into cultures?
Toxic to neuronal cultures
What other 2 genes were found to be associated with early onset AD>
Prenenilin 1 and 2
What did mutations in prenelinin cause?
Increased production of amyloid beta
What do the presenilins code for?
Two secretases beta (BACE) and gamma wich process beta-amyloid prescursor protein
How is the proteolysis of APP involved?
After APP produced it either produces neurtrophic, neuroprotective peptide or produces AB peptide
Depending on which secretase chops it first it can be good or bad
What happens when alpha-secretase (ADAM) cuts first and what happens when BACE doe?
ADAM - beneficial
BACE - not good and impairs function
How does cell-cell spread of amyloid-B happen?>
Produced exracellularly and wraps up in little vesicles which are taken up by other cells - propensity for damage to spread around the brain like a prion
What was shown in animal models for a therapy for amyloid hypo and what is the problem with it?
Inhibitor of B-secretase reduced about of Ab being produced
Work agains many other proteins
What has been suggested as another therapy for amyloid hypo?
Proteolysis of amyloid-b
Why are amploid plaques so bad?
Form clumps and hen attract other molecules and becomes resistant to degredation
What eznymes could be invovled in therapeutic degradation of amyloid?
Neprylysin and insulin degrading enzyme
What does neprilysin do?
Breaks down oligomers and breaks down into fragments
What do amyloid-b plaques do?
Might bind to post synaptic receptors affecting transmission
How do the amyloid and tau hypos mix?
Need interaction between Ab and tau to make MT transport work?
May form complexs
What do plaques and tau tangles cause in neurons
What is a gene associated with lae onset AD?
aPOLIPOROTEIN e - many variants with differing levels of death
Which variants of apolipoprotein E are the best and worst?
2 and 3 are good, 4 is bad
What is proposed to be the fuction of apolipoprotein E?
Clearance of cholesterol and possibly amyloid B and take it to blood
How could AD be linked to alzeimers>
May be to do with clearance of cholesterol
Mutations in insulin signalling increases risk of dementia
What is Liraglutide?
Diabetic drug that preserves mouse memory
How is oxidative stress suggested to be linked to AD?
Amyloid-B possibly protects cells for ROS?
(with diabetes) = problems with sugar and fat metabolism puts stress on mitochondria
How vaccination go with trying to help AD?
370 patients got inflammation of the meninges - microglia and t cells attacked the Ab42 vaccination
7 years later had lower amyloid b
Clinical trials of shorter peptides (long end was attacked)