ALZHEIMER'S DISEASE Flashcards
what is the main risk factors for Alzheimers disease?
age
APP, PSEN, ApoE mustations predispose people to an early onset of Alzheimers
what are the clinical symptoms of Alzheimers
memory loss * disorientation/ confusion language problems personality changes poor judgement
describe the major theory of Alzheimers pathophysiology
amyloid hypothesis
clumps of beta amyloid clumps found in people who have died of Alzheimers
normal:
alpha secretase enzyme cleaves the amyloid precursor protein. then gamma amylase cleaves the product and then the remaining products are removed
pathophsiological:
APP is cleaved by beta secretase instead of alpha first and this cleaves it at a slightly different site so it leaves a longer product within the membrane which is cleaved by gamma. instead of getting an inert product you get a product called eta amyloid.
this is not removed and they congregate within and outside the neurones (and other cells) and form plaques
describe the Tau hypothesis
normal:
within microtubules there are soluble Tau proteins present on axons which are important for assemply and stability of microtubules
patho
the tau proteins are hyperphosphorylated which make them insoluble
they then aggregate to form neurofibrillary tangles which are neurotoxic
also results in microtubule instability
describe the inflammation hypothesis
microglial cells increase their release of inflammatory mediators and cytotoxic proteins
there is and increased amount of phagocytosis
which reduces the levels of neuroprotective proteins
microglial cells can be activated by various mediators
indviduals who take ibuprofen for a long time have a decreased risk of Alzheimers
what are some drugs used to treat Alzheimers
anticholinesterases
eg donepezil, rivastigmine, galantamine
NMDA receptor blocker
eg, Memantine
what is the MOA of donepezil in treating Alzheimers?
reversible cholinesterase inhibitor
long plasma half life (administered once daily)
what is the MOA of rivastigmine?
pseudo- reversible acetylecholineseterase and butenlycholinesterase inhibitor.
inhibiting the bchE is not a good thing and accounts for some of the side effects.
what is the MOA of galantamine?
reversibe AChE inhibitor
also has affect directly on the alpha 7 nAChR and acts as an antagonist
this has a slightly more beneficia;l effect
why would increasing ACh be good for treating Alzheimers
an increase in ACh reverses the memory loss in patients with Alzheimers
almost immediate effect but lasts a maximum of 2 years
they treat the symptoms but not the underlying cause of the disease
what is the MOA of memantine?
non competitive NMDA receptor blocker with low channel affinity
long plasma half life
used in moderate-severe Alzheimers
only useful in excessive NMDA receptor activity which you get with more severe Alzheimers
what are some examples of failed treatments?
–>gamma secretase inhibitors
eg, tarenflurbil & semagacestat
failed as gamma secretase is also required in the physiological prossess
semagacestat is an example but it was found to increase the risk of skin cancer
–> drugs targeting the B amyloid plaques
eg bapineuzumab & solanezumab
antibodies made to act against the plaques
-big trial failure
–> Tau inhibitors
eg, Methylene blue
no money in the clinical trials and tends to make people turn blue
