Apolipoprotein E and Mimetics as Targets and Therapeutics for Alzheimer’s Disease
After age, the APOE4 genotype is the largest risk factor for Alzheimer’s disease (AD). We have developed a series of novel “COG” peptides that mimic the actions of full-length apolipoprotein-E3. Using multiple approaches, we show that COG1410 crosses the blood-brain barrier to provide anti-inflammatory and neuroprotective activities similar to those associated with APOE2- and APOE3-carrying individuals. Like holo-apoE3, COG112 and COG1410 stimulate neurite outgrowth and provide inhibition of inflammatory cytokine release that is independent of APOE-genotype of the treated cells. Using our CVN mouse model of AD that develops behavioral deficits, neuronal loss, amyloid plaques, and neurofibrillary tangle in a time-dependent manner, treatment with COG1410 significantly improves learning and memory behaviors, while decreasing neuronal loss, decreasing amyloid plaques, and decreasing neurofibrillary tangles. This desirable spectrum of disease ameliorating activities after COG treatments suggests a new approach for the treatment of Alzheimer’s and other APOE4-associated diseases.
