Journal of Alzheimers Disease & Parkinsonism
Open Access

Abstract

Humans are the only species that have multiple apolipoprotein-E genotypes, with APOE2, APOE3 and APOE4 being the most common. The APOE4 genotype is associated with a dramatic increase in susceptibility to acquiring Alzheimer?s disease. While reports vary, between 45% and 85% of all Alzheimer?s patients carry the APOE4 gene. Since APOE4 is inherited from birth, a variety of deficits in learning and memory abilities are beginning to be documented in ever-younger APOE4 carriers. Going the other way, APOE2 carriers are enriched in populations that live to be more than 100 years of age. We discovered that the APOE gene and its apolipoprotein-E products (apoE proteins) are master controllers of inflammation. Human APOE4 carriers and transgenic APOE4 mice have significantly greater responses to inflammatory stimuli than do APOE4-non-carriers. A rank order emerges where inflammatory responses follow a pattern of APOE4>APOE3>APOE2, the same rank order for Alzheimer?s disease. Using this knowledge, we created a series of apoE2-mimetic peptides that function as anti-inflammatory agents independent of the APOE genotype of the host. Using molecular techniques, we found that apoE and apoE-mimetics bind to Inhibitor #2 of Protein Phosphatase 2A (I2PP2A or SET). Bound apoE/mimetics antagonize I2PP2A/ SET to permit the re-activation of PP2A, a phosphatase that directly reduces inflammatory signaling pathways. Beyond inflammation, PP2A is better known as the key enzyme in the brain that dephosphorylates phosphorylated-tau/neurofibrillary tangles and in more recent reports, controls amyloid beta peptide levels. Using a variety of molecular methods, Iqbal and Wang have validated that increasing SET levels exacerbates Alzheimer?s pathology, while reducing SET levels ameliorates Alzheimer?s pathology. Building on these results, we tested our apoE-mimetics in the CVN transgenic mouse model of AD. CVN mice display age-dependent increases in amyloid plaques, neurofibrillary tangles, neuronal loss and behavioral deficits. Treatment of aged CVN mice displaying measurable disease characteristics with apoE-mimetic peptides dramatically reduced levels of brain inflammation, amyloid plaques and neurofibrillary tangles. Learning and memory behaviors were also significantly improved with apoE-mimetic treatment, as were the numbers of surviving hippocampal neurons. These data and others strongly support the use of neuroprotective apoE2-mimetics as potential therapeutics for the treatment of Alzheimer?s disease.

Biography