Flashcards in Alzheimer's Disease Deck (72):
What are the 4 characteristic brain hallmarks of alzheimer's disease?
Amyloid beta plaques
Neurofibrillary Tau tangles
What part of the brain does AD start in?
Lateral enterorhinal cortex
What regions does AD spread to after the lateral enterorhinal cortex?
cortical regions like the parietal cortex
What happens to the brain in AD?
Shrinks and loses grey matter.
Shutdown in brain metabolism and loss of activity.
How many amino acids long are Abeta plaques?
What is Tau part of?
the cytoskeleton- the microtubule stabilising protein
What are the microglia?
Resident brain macrophages. The immune cells in the brain
What do microglia do?
Clean up damaged neurones
Are advanced glycation end products intra or extra cellular?
What do advanced glycation end products reflect?
Sugar modification and oxidation through radical type damage of proteins in the brain
98% of AD cases are what?
Sporadic AD cases have an age of onset of what?
Carrying one copy of ApoE4 allele increases your risk of AD by what?
ApoE2 allele increases your risk of AD or protects you?
Gives you protection
Genetic forms of AD account for what % of the population?
less than 1%
What types of neurones are lost in AD?
Is the presynaptic or postsynaptic side of the neurone lost first?
What is the therapeutic idea with regards to cholinergic neurones?
Maintain acetylcholine in the synapse
How is acetylcholine maintained in the synapse?
By blocking acetylcholinesterase
What are the three acetykcholinesterase inhibitors?
Aricept (donepezil hydrocholride)
Acetylcholinesterase inhibitors are recommended for what form of AD?
Mild to moderate
what percentage of individuals show some benefit from acetylchilinesterase inhibitors for a limited amount of time?
What is Ebixa (memantine)?
NMDA receptor antagonist
What type of AD is memantine recommended for?
Moderate to severe
What system does Ebixa (memantine) target?
What are glutamate ion channels important in?
Over activation of glutamate ion channels is associated with what?
What does Ebixa (memantine) mimick?
What removes Ebixa (memantine) from the glutamate ion channel?
Action potential (not background activity)
Why is it important that Ebixa (memantine) doesn't permanently block glutamate channels?
They are needed for brain cognition and memory
What is the problem with MK-801?
It is not thrown out by synaptic activity so causes a global blockade. Side effects outweighed the benefits.
Os a combination of ChEI and Memantine prescribed routinely anywhere?
What do ChEI and Memantine do?
ChEI return signalling towards normal
Memantine reduces the background noise
What is the first step of the emyloid cascade hypothesis?
Changes in AB metabolism
-increase in total AB production
-increase in the Ab42/AB40 ratio
-reduced AB degradation/clearance
What happens after the initial changes in AB metabolism?
Oligomerisation of AB42 and initial AB42 deposits
What are the main steps of Amyloid cascade hypothesis?
Changes in AB metabolism
Oligomerisation and deposition of AB42 deposits
Oligomerisation and hyperphosphorylation of tau
Cell death associated with NT deficits
What happens if APP is cut by a-secretase?
No amyloid beta formation
What happens if APP is cut by b-secretase?
Leads to amyloid beta peptides
Where do almost all of the mutations in APP sit?
At or alongside the beta-secretase cleavage site
Where do all the familial mutations lie?
What is Semagacestat (LY450139)?
Why was the phase 3 trial for Semagacestat halted?
Failed to slow disease progression, made cognition worse and increased the risk of skin cancer
What is Verubecestat (MK-8931)?
What do initial phase 1 studies report for Verubecestat?
Reductions in AB40, !B42 and sAPPB in the CSF
What is the theory behind the use of anti-AB antibodies?
How does plaque breakdown occur with anti-AB antibodies?
Plaques are destroyed through Fc-mediated phagocytosis by microglia
How does the peripheral sink occur with anti-AB antibodies?
The formation of antigen-antibody complexes in the periphery sequesters amyloid away from the brain
How does 'aggregation inhibition' occur with anti-AB antibodies?
Formation of antigen-antibody complexes prevents amyloid beta from accumulating in plaques.
What are the two forms of active immunisation?
Immunisation with intact AB42 peptide
Immunisation with AB fragments
What is passive immunisation?
Immunisation with anti-AB antibodies
What type of immunisationis AN1792?
What is AN1792?
Aggregated synthetic human AB1-42
Why was the AN1792 trial halted?
18 patients developed meningoencephalitis
What was the AN1792 trial result?
Halted due to meningoencephalitis,
Clearance of cortical amyloid plaques
No clear evidence of clinical response
What type of immunisation is Bapineuzumab?
What is Bapineuzumab?
A monoclonal humanised antibody which recognises AB1-5
What was the outcome of Bapuneuzumab?
Reduction in cerebral AB load
Limited evidence of clinical benefit
What type of immunisation is Solanezumab?
What is Solanezumab?
A humanised monocloncal antibody which preferentially binds to soluble forms of AB (AB13-28)
What did the Solanezumab trial fail?
Failed to reach endpoints
What type of immunisation is Aducanumab?
What is Aducanumab?
A human monoclonal antibody
What do mutations in Tau lead to?
Why is Tau better for targeting than AB?
It correlates much better with the appearance of symptoms
What is Rember?
Tau aggregation inhibitor
What are two drugs which target tau pathology?
What adverse effect did GSK3B inhibitors cause?
How do we reduce tau pathology?
What was the outcome of the trials for the first drug to target tau tangles?
Reduced brain shrinkage
Scores on cognition and performance significantly improved
What are the 6 targets for disease progression?
Unfolded protein response
When do AB changes occur?
10/20 years before you see any symptoms