Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism

There are two distinct viewpoints on the association of the inheritance of apolipoprotein E (APOE) alleles and the age of onset distribution of Alzheimer's disease (AD): genetic and phenotypic expression. There have been multiple corroborations of the APOE-epsilon 4 association with Alzheimer's disease in populations around the world in clinic based studies as well as emerging epidemiological studies. The genetic data do not imply mechanism of pathogenesis. The phenotypic expression of AD has been based in theories based on amyloid plaques or neurofibrillary tangles. ApoE protein interacts with both beta-amyloid and tau in an isoform-specific manner. The interaction with tau had been thought to be an in vitro artifact, since apoE had not been previously localized to the neuronal cytoplasm. Immuno-EM studies have localized apoE in neuronal cytoplasm. ApoE3 interacts with both tau and MAP2c at the microtubule binding repeat domain under conditions in which apoE4 is less tightly bound. These data further support a hypothesis that apoE3 (and apoE2) protect the microtubule binding domain of tau from binding to itself to form paired helical filaments and neurofibrillary tangles, while protecting the site for microtubule stabilizing interactions with beta-tubulin. These data are supported by recent data from APOE knock-out mice demonstrating dendritic alterations leading to synaptic simplification similar to that observed in AD.