week 9 - synaptic dysfunction in alzheimers Flashcards
what are the two main theories of alzheimers disease?
Amyloid beta plaques
Neurofibillary tangles
What happens as the disease progresses?
Plaques and tangles spread through the brain. (starts in hippocampus and spreads through cortex. The cerebellum is generally spared)
Amyloid plaques tend to occur before the neurofibrillary tangles
Neurons die
The brain starts to atrophy, particuarly in the hippocampus
what is the familial alzheimers disease
mutation in the gene that codes for b-amyloid precursor protein
also associated with increased procudtion of amyloid
what is the amyloid precursor hypothesis?
amyloid deposition leads to pTAU hyperphosporylation which leads to tangle formation which leads to cell death
evidence: you commonly see amyloid deposition in normal individuals, but all individuals with amyloid deposition AND pTAU have cognitive impairment
describe app protein
it gets cleaved by B-secretase.
It can then get chopped again which results in a fragment called a-beta
however it can also get chopped again in a different way which doesn’t form toxic deposits
b secretase chops extracellularly, so for APP to get chopped it has to get shipped out the cell
what is the wnt pathway
Wnt is a secreted ligand
It binds to receptors, the main receptor it binds to is called frizzle
go into more detail about the Wnt pathway, read up on this
also read up on the wnt-catenin pathway
what is the normal role of beta-catenin?
as an adhesion molecule that sticks cells together
what is the wnt planar cell polarity pathway? (PCP pathway)
If you have a sheet of epithelia that looks identical, it is actually polarized
this pathway determines the planar orientation of cells
if this gets messed up in cells with bristles or hairs, e.g in the inner ear, then the hairs get messed up and you become deaf because the bristols turn up in different directions
What is the relationship between DKK1 and AB?
When they silence DKK1, A-beta becomes no longer neurotoxic!!’
why? Because DKK blocks LRP-6 which is a neccesrcary co-receptor for canonical wnt signalling to occur. This removes it from frizzled, causing a non canonical wnt pathway to be activated whcih
SO.. A beta and DKK activate elements of oa non-canonical Wnt-PCP pathway
what is DKK1?
find out
what has bioinformatic analysis showed?
that a lot of the pathways identified in a DKK treated tanscriptome have things in common with the alzheimers disease transcriptiomes
what could be the role of wnt-PCP in alzheimers
Wnt-PCP plays a key role in synaptic plasticity and dendritic spine formaiton
APP is a Wnt-PCP component. It binds frizzled and Vangle2
what happens if you treat dendritic spines with a-beta and dkkk?
if you treat dendritic spines with a-beta you lose the spines
so does treating with dkk1
however if you silence dkk, that protects against AB-related synapse loss
however if you go down the wnt-pcp pathway, you see DAM1. If you silence dam-1 then you also block the dkk-driven spine loss
what can help block ab and dkk1 driven spine loss?
ROCK inhibitor Fasudil
it blocks ab and dkk1 induced spine loss
CONCLUSIONS OF THE EXPERIMENT
- APP is a component of canonical and non-canonical wnt receptors
- Dkk1 one causes a switch from the canonical wnt signalling to non-canonical ent-PCP signalling
- This de-stabalises synaptic junctions causing dissasembly
- When the non-canonical Wnt-PCP pathway is favoured, MORE a-beta is made!
- A-beta makes dkk1, which then turns on more of the Wnt-PCP pathway
- This means there might be a feedback loop, where a-beta accelerates its own productionn
- Faudasil could be a treatment. In rat primary neurons as spines are lost AB levels increase, and faudasil blocks both. Faudasil also saw a massive reduction in AB plaques
