@article{8a4a055c8d4048dbb588a3ede355daa5,
title = "Vascular ApoE4 Impairs Behavior by Modulating Gliovascular Function",
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.",
keywords = "APOE, Alzheimer's disease, gliovascular function, single-cell RNA sequencing, vascular mural cells",
author = "Yu Yamazaki and Liu, {Chia Chen} and Akari Yamazaki and Francis Shue and Martens, {Yuka A.} and Yuanxin Chen and Wenhui Qiao and Aishe Kurti and Hiroshi Oue and Yingxue Ren and Ying Li and Tomonori Aikawa and Yesesri Cherukuri and Fryer, {John D.} and Asmann, {Yan W.} and Kim, {Betty Y.S.} and Takahisa Kanekiyo and Guojun Bu",
note = "Funding Information: The authors thank Dr. Laura Lewis-Tuffin for technical support. This work was supported by the National Institutes of Health (NIH) (grants R37AG027924, RF1AG051504, RF1AG057181, P50AG016574, and RF1AG046205 to G.B.; grant R01AG051574 to T.K.; and grant R01AG062110 to C.-C.L.), the Cure Alzheimer's Fund (G.B.), the American Heart Association (grant 15SDG22460003 to T.K. and fellowship 17POST33410227 to Y.Y.), and the Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program (grant 7AZ22 to T.K. and grant 8AZ07 to C.-C.L.). Y.Y. C.-C.L, A.Y. F.S. Y.A.M. Y. Chen, W.Q. A.K. and H.O. performed experiments; T.A. J.D.F. and B.Y.S.K. provided reagents and materials; Y.Y. F.S. Y. Chen, W.Q. Y.R. Y.L. Y. Cherukuri, and Y.W.A. analyzed data; and Y.Y. C.-C.L. T.K. and G.B. wrote the manuscript, with input from all authors. The authors declare no competing interests. Funding Information: The authors thank Dr. Laura Lewis-Tuffin for technical support. This work was supported by the National Institutes of Health (NIH) (grants R37AG027924 , RF1AG051504 , RF1AG057181 , P50AG016574 , and RF1AG046205 to G.B.; grant R01AG051574 to T.K.; and grant R01AG062110 to C.-C.L.), the Cure Alzheimer's Fund (G.B.), the American Heart Association (grant 15SDG22460003 to T.K. and fellowship 17POST33410227 to Y.Y.), and the Florida Department of Health Ed and Ethel Moore Alzheimer{\textquoteright}s Disease Research Program (grant 7AZ22 to T.K. and grant 8AZ07 to C.-C.L.). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2021",
month = feb,
day = "3",
doi = "10.1016/j.neuron.2020.11.019",
language = "English (US)",
volume = "109",
pages = "438--447.e6",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "3",
}