Astrocytic expression of the Alzheimer's disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models.

ApoEe4 is a major genetic risk factor for Alzheimer’s disease (AD), a disease hallmarked by extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The presence of the ApoEe4 allele is associated with increased Aβ deposition and a role for ApoEe4 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 ApoEe4 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 ApoEe4 to increase tau aggregation could be inhibited by an ApoEe4-specific antibody. This study indicates that astrocytic expression of ApoEe4 can potentiate tau aggregation and phosphorylation within neurons and supports a gain of toxic function hypothesis for the effect of hApoEe4 on tau.