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

التفاصيل البيبلوغرافية
العنوان: Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.
المؤلفون: Liu CC; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. liu.chiachen@mayo.edu., Zhao J; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Fu Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Inoue Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Ren Y; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., Chen Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Doss SV; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Shue F; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Jeevaratnam S; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Bastea L; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA., Wang N; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Martens YA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Qiao W; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Wang M; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA., Zhao N; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Jia L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Yamazaki Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Yamazaki A; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Rosenberg CL; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Wang Z; Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA., Kong D; Department of Biology, University of North Dakota, Grand Forks, ND, USA., Li Z; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Kuchenbecker LA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Trottier ZA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Felton L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Rogers J; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Quicksall ZS; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Linares C; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Knight J; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Chen Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Kurti A; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Kanekiyo T; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Fryer JD; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Asmann YW; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., Storz P; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA., Wang X; Department of Biology, University of North Dakota, Grand Forks, ND, USA., Peng J; Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA., Zhang B; Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Kim BYS; Department of Neurosurgery, The Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Bu G; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Guojun.Bu@molecularneurodegeneration.org.
المصدر: Nature neuroscience [Nat Neurosci] 2022 Aug; Vol. 25 (8), pp. 1020-1033. Date of Electronic Publication: 2022 Aug 01.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 9809671 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1726 (Electronic) Linking ISSN: 10976256 NLM ISO Abbreviation: Nat Neurosci Subsets: MEDLINE
أسماء مطبوعة: Publication: <2002->: New York, NY : Nature Publishing Group
Original Publication: New York, NY : Nature America Inc., c1998-
مواضيع طبية MeSH: Alzheimer Disease*/metabolism , Induced Pluripotent Stem Cells*/metabolism, Animals ; Apolipoprotein E3/genetics ; Apolipoprotein E3/metabolism ; Apolipoprotein E4/genetics ; Apolipoprotein E4/metabolism ; Apolipoproteins E/genetics ; Brain/metabolism ; Cognition ; Humans ; Mice ; Mice, Transgenic ; Protein Isoforms/metabolism
مستخلص: 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
التعليقات: Comment in: Neurosci Bull. 2023 Aug;39(8):1330-1332. (PMID: 37093447)
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معلومات مُعتمدة: P30 CA016672 United States CA NCI NIH HHS; RF1 AG054014 United States AG NIA NIH HHS; U01 AG052411 United States AG NIA NIH HHS; U01 AG046170 United States AG NIA NIH HHS; RF1 AG062110 United States AG NIA NIH HHS; R37 AG027924 United States AG NIA NIH HHS; RF1 AG046205 United States AG NIA NIH HHS; U19 AG069701 United States AG NIA NIH HHS; RF1 AG057181 United States AG NIA NIH HHS; R21 AG057981 United States AG NIA NIH HHS
المشرفين على المادة: 0 (Apolipoprotein E3)
0 (Apolipoprotein E4)
0 (Apolipoproteins E)
0 (Protein Isoforms)
تواريخ الأحداث: Date Created: 20220801 Date Completed: 20220803 Latest Revision: 20240503
رمز التحديث: 20240503
مُعرف محوري في PubMed: PMC10009873
DOI: 10.1038/s41593-022-01127-0
PMID: 35915180
قاعدة البيانات: MEDLINE
الوصف
تدمد:1546-1726
DOI:10.1038/s41593-022-01127-0