10: vaccines

Question 1

APP: stands for? what? where? important for?

Answer 1

amyloid precursor protein. membrane protein, sits in membrane and extends outward. neuronal growth, survival, repair.

Question 2

what happens to APP?

Answer 2

secretases cut APP into fragments: releases beta-amyloid (beta and gamma secretase)

Question 3

idea of vaccine: 3 effects?

Answer 3

tangles/neurites unaffected. disappearance of plaques (destroyed by microglia). inflammatory cells surround blood vessel with amyloid

Question 4

transgenic models of AD: 3 anatomical things? behaviour? what’s missing?

Answer 4

abundant mutant b-APP, diffuse AB deposits in brain, abnormal and dysmorphic synapses. variable behaviour deficits. no neurofibrillary pathology

Question 5

vaccinate PDAPP mice: what happens?

Answer 5

give vaccine before or after development of pathology: see less amyloid deposition or memory deficits

Question 6

3 possible mechanisms of action of anti-AB antibodies?

Answer 6

plaque breakdown. peripheral sink. aggregation inhibitor

Question 7

anti-AB antibodies: plaque breakdown?

Answer 7

plaques destroyed through Fc-mediated phagocytosis by microglial cells

Question 8

anti-AB antibodies: peripheral sink?

Answer 8

formation of antigen-antibody complex in periphery (blood) sequesters amyloid from the brain and prevents deposition of new plaques

Question 9

anti-AB antibodies: aggregation inhibitor?

Answer 9

formation of antigen-antibody complexes prevents amyloid accumulating in the plaques. only non-toxic monomeric amyloid species left.

Question 10

AN1792 QS 21 phase 1?

Answer 10

AD vaccine: passive immunization on mild to moderate AD, showed antibody response and safe

Question 11

AN1792: Phase IIa what happened?

Answer 11

18 pts with meningoencephalitis so trial stopped, unacceptable side effects

Question 12

AN1792: results?

Answer 12

patients that generated antibodies showed slower rates of memory decline. even patients with mengoencephalitis showed beneficial effects

Question 13

autopsy findings of patients with immunization with AB - what changed and what didn’t?

Answer 13

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

Question 14

autopsy findings of patients with immunization with AB - what persisted? immune response?

Answer 14

tau pathology and cerebral blood vessel amyloid persisted. T-lymphocyte mingoencephalitis. cerebral white matter showed infiltration by macrophages

Question 15

vaccines in the future: what should we use? most important?

Answer 15

better antibodies - more directed at fragments of AB, passive immunization. most important is selection of appropriate patients

Question 16

future of vaccine: what is a concern? also want to induct __ not__?

Answer 16

meningo encephalitis. induction of Th2 type cells, not Th1 type cells.

Question 17

bapineuzumab: what?

Answer 17

humanized anti-AB mnoclonal antibody against specific domain of AB; passive immunization

Question 18

bapineuzumab: results?

Answer 18

phase II trials show improvement in ApoE4 non carriers, brain edema but resolved, phase Ii reported no benefit

Question 19

solaneuzumab: what

Answer 19

another humanized anti-AB monoclonal antibody agianst a specific AB domain

Question 20

solaneuzumab: results?

Answer 20

phase II: no benefit in moderate to severe, but benefit in mild AD patients

Question 21

summary: what is an attractive therapeutic strategy for AD? why?

Answer 21

immunotherapy: preclinical studies show both active + passive approaches can remove amyloid and also improve cognitive function

Question 22

significant side effect of all passive immunization strategies targeting aggregated AB is?

Answer 22

amyloid related imaging abnormalities, edema

Question 23

what about tau vaccines?

Answer 23

non phophoryated phosphorylated tau vaccines entering phase I testing. active/passive immunization targeting both amyloid + tau pathology simultaneously holds potential

Question 24

summary: possible approaches (4)

Answer 24

secretase inhibitors to stop AB production. deposition inhibitors to stop aggregation. increase clearance with antibodies. block effects on neuronal loss.