Astrocytic expression of the Alzheimer's disease risk allele, ApoE?4, potentiates neuronal tau pathology in multiple preclinical models.

ABSTRACT: ApoE?4 is a major genetic risk factor for Alzheimer's disease (AD), a disease hallmarked by extracellular amyloid-beta (A?) plaques and intracellular neurofibrillary tangles (NFTs). The presence of the ApoE?4 allele is associated with increased A? deposition and a role for ApoE?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?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?4 to increase tau aggregation could be inhibited by an ApoE?4-specific antibody. This study indicates that astrocytic expression of ApoE?4 can potentiate tau aggregation and phosphorylation within neurons and supports a gain of toxic function hypothesis for the effect of hApoE?4 on tau.

SUBMITTER: Jablonski AM 

PROVIDER: S-EPMC7873246 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature