110 A molecular model of Alzheimer’s disease Hie AP24534 mouse amyloid cascade hypothesis can now be elaborated in some detail. Normally, APP is processed via both amyloidogenic and nonamyloidogenic routes. A number of events perturb the balance to a greater or lesser extent. Mutations in APP profoundly bias metabolism toward the amyloid ogenic route, and head injury increases amyloidogenesis perhaps by simply increasing the total levels of APP expression. Somehow, amyloid production increases tau phosphorylation. Perhaps the most likely hypothesis at the present time is that
amyloid peptide increases GSK-3 activity, although whether this is through intra- or extracellular amyloid is uncertain. GSK-3 activity increases tau phosphorylation, which then Inhibitors,research,lifescience,medical fails to bind Inhibitors,research,lifescience,medical microtubules, resulting in loss of microtubule stability and accumulation of tau in the cell body, which predisposes to tau aggregation. Mutations in tau also cause increased aggregation and reduced binding to microtubules in a manner analogous to phosphorylation. Mutations in presenilins certainly cause increased amyloid production
from APP and might also have other effects including through Notch and/or Wingless signaling that might impact upon tau phosphorylation. Inhibitors,research,lifescience,medical What else is known about. AD that impacts upon the cascade? Most, obviously omitted from this scheme is apolipoprotein E (apo E), the only confirmed genetic association with late-onset AD.111,112 Studies of the biology of apo E have proved very difficult Inhibitors,research,lifescience,medical to conduct, with disparate results partly accounted for by technical differences in the preparation of apo E protein. Apo E has been shown to interact with amyloid peptide, but. some studies show greater interaction with
apo E2 and others with apo E4.113-115 Depending upon the true result in vivo, apo E binding might, enhance Inhibitors,research,lifescience,medical amyloid fibrillization and hence plaque formation, or enhance amyloid clearance and hence plaque destruction. Alternatively, apo E might affect, tau phosphorylation. Tau binds apo E in an isoform-dependent manner, and it was hypothesized that such binding would alter the phosphorylation state of tau.116-118 We have confirmed of this is in fact the case (unpublished observations), although whether this occurs in vivo is uncertain. Indeed it is not even known if tau and apo E would meet in vivo. Some studies suggest extracellular apo E is internalized into the cytoplasm compartment.119,120 At least one study suggests it is not.121 In neurons, apo E appears to be in the cytoplasm, but this might result from expression of apo E in a form that is not immediately secreted.122-124 Other cellular approaches do suggest tau alters microtubules and affects neuronal growth, both compatible with, but not proving, an effect of apo E on tau.120,125-127 It might be that apo E has no effect on either tau or amyloid, affecting instead local cholesterol transport, neuronal viability, and resilience to damage.
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