Peripheral apoE4 enhances Alzheimer’s pathology and impairs cognition by compromising cerebrovascular function

Chia Chen Liu, Jing Zhao, Yuan Fu, Yasuteru Inoue, Yingxue Ren, Yuanxin Chen, Sydney V. Doss, Francis Shue, Suren Jeevaratnam, Ligia Bastea, Na Wang, Yuka A. Martens, Wenhui Qiao, Minghui Wang, Na Zhao, Lin Jia, Yu Yamazaki, Akari Yamazaki, Cassandra L. Rosenberg, Zhen WangDehui Kong, Zonghua Li, Lindsey A. Kuchenbecker, Zachary A. Trottier, Lindsey Felton, Justin Rogers, Zachary S. Quicksall, Cynthia Linares, Joshua Knight, Yixing Chen, Aishe Kurti, Takahisa Kanekiyo, John D. Fryer, Yan W. Asmann, Peter Storz, Xusheng Wang, Junmin Peng, Bin Zhang, Y S Betty Kim, Guojun Bu

Research output: Contribution to journalArticlepeer-review

Abstract

The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer’s disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood–brain barrier, differentially impact Alzheimer’s disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer’s disease.

Original languageEnglish (US)
Pages (from-to)1020-1033
Number of pages14
JournalNature Neuroscience
Volume25
Issue number8
DOIs
StatePublished - Aug 2022

ASJC Scopus subject areas

  • Neuroscience(all)

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