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

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...

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Published in:Nature neuroscience 2022-08, Vol.25 (8), p.1020-1033
Main Authors: Liu, Chia-Chen, Zhao, Jing, Fu, Yuan, Inoue, Yasuteru, Ren, Yingxue, Chen, Yuanxin, Doss, Sydney V, Shue, Francis, Jeevaratnam, Suren, Bastea, Ligia, Wang, Na, Martens, Yuka A, Qiao, Wenhui, Wang, Minghui, Zhao, Na, Jia, Lin, Yamazaki, Yu, Yamazaki, Akari, Rosenberg, Cassandra L, Wang, Zhen, Kong, Dehui, Li, Zonghua, Kuchenbecker, Lindsey A, Trottier, Zachary A, Felton, Lindsey, Rogers, Justin, Quicksall, Zachary S, Linares, Cynthia, Knight, Joshua, Chen, Yixing, Kurti, Aishe, Kanekiyo, Takahisa, Fryer, John D, Asmann, Yan W, Storz, Peter, Wang, Xusheng, Peng, Junmin, Zhang, Bin, Kim, Betty Y S, Bu, Guojun
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Alzheimer's disease
Animal models
Animals
Apolipoprotein E
Apolipoprotein E3 - genetics
Apolipoprotein E3 - metabolism
Apolipoprotein E4
Apolipoprotein E4 - genetics
Apolipoprotein E4 - metabolism
Apolipoproteins E - genetics
Blood vessels
Blood-brain barrier
Brain - metabolism
Cell adhesion
Cognition
Cognition & reasoning
Complement activation
Endothelial cells
Functionals
Gliosis
Humans
Induced Pluripotent Stem Cells - metabolism
Integrity
Isoforms
Lipid metabolism
Liver
Liver diseases
Mice
Mice, Transgenic
Neurodegenerative diseases
Pathogenesis
Pathology
Plasma
Pluripotency
Protein Isoforms - metabolism
Proteomes
Risk analysis
Risk factors
Stem cells
Synaptic plasticity
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Summary: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.
ISSN:1097-6256
1546-1726
DOI:10.1038/s41593-022-01127-0