Astrocytic Expression Of The Alzheimer'S Disease Risk Allele, Apoe Epsilon 4, Potentiates Neuronal Tau Pathology In Multiple Preclinical Models

ApoE epsilon 4 is a major genetic risk factor for Alzheimer's disease (AD), a disease hallmarked by extracellular amyloid-beta (A beta) plaques and intracellular neurofibrillary tangles (NFTs). The presence of the ApoE epsilon 4 allele is associated with increased A beta deposition and a role for ApoE epsilon 4 in the potentiation of tau pathology has recently emerged. This study focused on comparing the effects of adeno-associated virus (AAV)-mediated overexpression of the three predominant human ApoE isoforms within astrocytes. The isoform-specific effects of human ApoE were evaluated within in vitro models of tau pathology within neuron/astrocyte co-cultures, as well as in a transgenic tau mouse model. Tau aggregation, accumulation, and phosphorylation were measured to determine if the three isoforms of human ApoE had differential effects on tau. Astrocytic overexpression of the human ApoE epsilon 4 allele increased phosphorylation and misfolding of overexpressed neuronal tau in multiple models, including the aggregation and accumulation of added tau oligomers, in an isoform-specific manner. The ability of ApoE epsilon 4 to increase tau aggregation could be inhibited by an ApoE epsilon 4-specific antibody. This study indicates that astrocytic expression of ApoE epsilon 4 can potentiate tau aggregation and phosphorylation within neurons and supports a gain of toxic function hypothesis for the effect of hApoE epsilon 4 on tau.