Vascular ApoE4 Impairs Behavior by Modulating Gliovascular Function.
Neuron
; 109(3): 438-447.e6, 2021 02 03.
Article
em En
| MEDLINE
| ID: mdl-33321072
ABSTRACT
The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and multiple vascular conditions. ApoE is abundantly expressed in multiple brain cell types, including astrocytes, microglia, and vascular mural cells (VMCs). Here, we show that VMC-specific expression of apoE4 in mice impairs behavior and cerebrovascular function. Expression of either apoE3 or apoE4 in VMCs was sufficient to rescue the hypercholesterolemia and atherosclerosis phenotypes seen in Apoe knockout mice. Intriguingly, vascular expression of apoE4, but not apoE3, reduced arteriole blood flow, impaired spatial learning, and increased anxiety-like phenotypes. Single-cell RNA sequencing of vascular and glial cells revealed that apoE4 in VMCs was associated with astrocyte activation, while apoE3 was linked to angiogenic signature in pericytes. Together, our data support cell-autonomous effects of vascular apoE on brain homeostasis in an isoform-dependent manner, suggesting a critical contribution of vascular apoE to AD pathogenesis.
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Base de dados:
MEDLINE
Assunto principal:
Arteríolas
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Encéfalo
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Astrócitos
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Apolipoproteína E4
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Gliose
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article