Vascular apoE4 Impairs Brain Cognition by Modulating Glio-Vascular Functions

Abstract

The e4 allele of the apolipoprotein E gene (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD) compared to the common e3 allele. Because APOE4 is also associated with an increased risk for several vascular conditions including small vessel disease and vascular cognitive impairment (VCI), apoE4 effects on cerebrovasculature might be a converging pathway impacting brain homeostasis. As apoE is abundantly expressed in multiple brain cell types including astrocytes, microglia, and vascular mural cells (VMCs), defining the in vivo effect of apoE4 expressed by individual cell types is critical for addressing its pathogenic mechanism. Here, using conditional mouse models, we show that VMC-specific apoE4 expression impairs cognition and glio-vascular functions. Expression of either apoE3 or apoE4 in VMCs was sufficient to rescue the hypercholesterolemia and atherosclerosis phenotypes seen in the Apoe-knockout mice. Intriguingly, vascular specific expression of apoE4, but not apoE3, led to decreased arteriole blood flow, impaired spatial learning, and increased anxiety-like phenotypes. Single cell RNA sequencing of vascular and glial cells isolated from these mice revealed that conditional expression of apoE4 in VMCs was associated with astrocyte activation while expression of apoE3 in VMCs was associated with angiogenic signatures in pericytes. Together, our data support cell-autonomous effects of vascular apoE on multiple brain homeostatic processes in an isoform-dependent manner, suggesting a critical contribution of vascular apoE in the pathogenesis of AD and VCI.