10: vaccines Flashcards
APP: stands for? what? where? important for?
amyloid precursor protein. membrane protein, sits in membrane and extends outward. neuronal growth, survival, repair.
what happens to APP?
secretases cut APP into fragments: releases beta-amyloid (beta and gamma secretase)
idea of vaccine: 3 effects?
tangles/neurites unaffected. disappearance of plaques (destroyed by microglia). inflammatory cells surround blood vessel with amyloid
transgenic models of AD: 3 anatomical things? behaviour? what’s missing?
abundant mutant b-APP, diffuse AB deposits in brain, abnormal and dysmorphic synapses. variable behaviour deficits. no neurofibrillary pathology
vaccinate PDAPP mice: what happens?
give vaccine before or after development of pathology: see less amyloid deposition or memory deficits
3 possible mechanisms of action of anti-AB antibodies?
plaque breakdown. peripheral sink. aggregation inhibitor
anti-AB antibodies: plaque breakdown?
plaques destroyed through Fc-mediated phagocytosis by microglial cells
anti-AB antibodies: peripheral sink?
formation of antigen-antibody complex in periphery (blood) sequesters amyloid from the brain and prevents deposition of new plaques
anti-AB antibodies: aggregation inhibitor?
formation of antigen-antibody complexes prevents amyloid accumulating in the plaques. only non-toxic monomeric amyloid species left.
AN1792 QS 21 phase 1?
AD vaccine: passive immunization on mild to moderate AD, showed antibody response and safe
AN1792: Phase IIa what happened?
18 pts with meningoencephalitis so trial stopped, unacceptable side effects
AN1792: results?
patients that generated antibodies showed slower rates of memory decline. even patients with mengoencephalitis showed beneficial effects
autopsy findings of patients with immunization with AB - what changed and what didn’t?
extensive neocortex with very few amyloid plaques. tangles and neuropil threads, cerebral amyloid angioapthy similar to unimmunized pts. presence of microglia in areas devoid of plaques
autopsy findings of patients with immunization with AB - what persisted? immune response?
tau pathology and cerebral blood vessel amyloid persisted. T-lymphocyte mingoencephalitis. cerebral white matter showed infiltration by macrophages
vaccines in the future: what should we use? most important?
better antibodies - more directed at fragments of AB, passive immunization. most important is selection of appropriate patients
future of vaccine: what is a concern? also want to induct __ not__?
meningo encephalitis. induction of Th2 type cells, not Th1 type cells.
bapineuzumab: what?
humanized anti-AB mnoclonal antibody against specific domain of AB; passive immunization
bapineuzumab: results?
phase II trials show improvement in ApoE4 non carriers, brain edema but resolved, phase Ii reported no benefit
solaneuzumab: what
another humanized anti-AB monoclonal antibody agianst a specific AB domain
solaneuzumab: results?
phase II: no benefit in moderate to severe, but benefit in mild AD patients
summary: what is an attractive therapeutic strategy for AD? why?
immunotherapy: preclinical studies show both active + passive approaches can remove amyloid and also improve cognitive function
significant side effect of all passive immunization strategies targeting aggregated AB is?
amyloid related imaging abnormalities, edema
what about tau vaccines?
non phophoryated phosphorylated tau vaccines entering phase I testing. active/passive immunization targeting both amyloid + tau pathology simultaneously holds potential
summary: possible approaches (4)
secretase inhibitors to stop AB production. deposition inhibitors to stop aggregation. increase clearance with antibodies. block effects on neuronal loss.
