TY - JOUR
T1 - Peripheral apoE4 enhances Alzheimer’s pathology and impairs cognition by compromising cerebrovascular function
AU - Liu, Chia Chen
AU - Zhao, Jing
AU - Fu, Yuan
AU - Inoue, Yasuteru
AU - Ren, Yingxue
AU - Chen, Yuanxin
AU - Doss, Sydney V.
AU - Shue, Francis
AU - Jeevaratnam, Suren
AU - Bastea, Ligia
AU - Wang, Na
AU - Martens, Yuka A.
AU - Qiao, Wenhui
AU - Wang, Minghui
AU - Zhao, Na
AU - Jia, Lin
AU - Yamazaki, Yu
AU - Yamazaki, Akari
AU - Rosenberg, Cassandra L.
AU - Wang, Zhen
AU - Kong, Dehui
AU - Li, Zonghua
AU - Kuchenbecker, Lindsey A.
AU - Trottier, Zachary A.
AU - Felton, Lindsey
AU - Rogers, Justin
AU - Quicksall, Zachary S.
AU - Linares, Cynthia
AU - Knight, Joshua
AU - Chen, Yixing
AU - Kurti, Aishe
AU - Kanekiyo, Takahisa
AU - Fryer, John D.
AU - Asmann, Yan W.
AU - Storz, Peter
AU - Wang, Xusheng
AU - Peng, Junmin
AU - Zhang, Bin
AU - Kim, Betty Y.S.
AU - Bu, Guojun
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85135241677&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85135241677&partnerID=8YFLogxK
U2 - 10.1038/s41593-022-01127-0
DO - 10.1038/s41593-022-01127-0
M3 - Article
C2 - 35915180
AN - SCOPUS:85135241677
SN - 1097-6256
VL - 25
SP - 1020
EP - 1033
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 8
ER -