Journal
CURRENT ALZHEIMER RESEARCH
Volume 13, Issue 8, Pages 918-929Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1567205013666160404120817
Keywords
Alzheimer's disease; apolipoprotein E4 (apoE4); antibodies; behavior; immunotherapy; targeted replacement mice; tau
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Funding
- Legacy Heritage Bio-Medical Program of the Israel Science Foundation [1575/14]
- Joseph K. and Inez Eichenbaum Foundation
- Harold and Eleanore Foonberg Foundation
- Teva Pharmaceutical Industries Ltd as part of the Israeli National Network of Excellence in Neuroscience (NNE)
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ApolipoproteinE4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and as such is a promising therapeutic target. This study examined the extent to which the pathological effects of apoE4 can be counteracted in vivo utilizing an immunological approach in which anti-apoE4 antibodies are applied peripherally by i.p. injections into apoE4-targeted replacement mice. Prerequisites for the successful pursuit of this objective are the availability of antibodies that specifically bind brain apoE4 and not apoE3, and demonstrating that direct application of these antibodies into the brain can counteract the effects of apoE4. Accordingly, it was shown that the anti-apoE4 monoclonal antibody (mAb) 9D11 binds specifically to brain apoE4 and not apoE3. Direct i.c.v. application of mAb 9D11 prevented the apoE4-driven accumulation of A beta in hippocampal neurons following activation of the amyloid cascade by inhibiting the A beta-degrading enzyme neprilysin. These findings provide a proof-of-concept that anti-apoE4 mAb 9D11, when introduced into the brain, can counteract the apoE4 effects in vivo. Subsequent experiments, utilizing repeated i.p. injections of mAb 9D11, resulted in the formation of apoE/IgG complexes specifically in apoE4 mice. This was associated with reversal of the cognitive impairments of apoE4 in the Morris water maze and the novel object recognition test as well as with reversal of key apoE4-driven pathologies including the hyperphosphorylated tau and the reduced levels of the apoER2 receptor. These results indicate that anti-apoE4 immunotherapy counteracts the cognitive and brain pathological effects of apoE4, and suggest that such an approach could also benefit human apoE4 carriers.
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