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Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease.

TitleIntegrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease.
Publication TypeJournal Article
Year of Publication2021
AuthorsPanitch R, Hu J, Chung J, Zhu C, Meng G, Xia W, Bennett DA, Lunetta KL, Ikezu T, Au R, Stein TD, Farrer LA, Jun GR
JournalMol Psychiatry
Volume26
Issue10
Pagination6054-6064
Date Published2021 Oct
ISSN1476-5578
Abstract

Mechanisms underlying the protective effect of apolipoprotein E (APOE) ε2 against Alzheimer disease (AD) are not well understood. We analyzed gene expression data derived from autopsied brains donated by 982 individuals including 135 APOE ɛ2/ɛ3 carriers. Complement pathway genes C4A and C4B were among the most significantly differentially expressed genes between ɛ2/ɛ3 AD cases and controls. We also identified an APOE ε2/ε3 AD-specific co-expression network enriched for astrocytes, oligodendrocytes and oligodendrocyte progenitor cells containing the genes C4A, C4B, and HSPA2. These genes were significantly associated with the ratio of phosphorylated tau at position 231 to total Tau but not with amyloid-β 42 level, suggesting this APOE ɛ2 related co-expression network may primarily be involved with tau pathology. HSPA2 expression was oligodendrocyte-specific and significantly associated with C4B protein. Our findings provide the first evidence of a crucial role of the complement pathway in the protective effect of APOE ε2 for AD.

DOI10.1038/s41380-021-01266-z
Pubmed Linkhttps://www.ncbi.nlm.nih.gov/pubmed/34480088?dopt=Abstract
page_expoExternal
Alternate JournalMol Psychiatry
PubMed ID34480088
PubMed Central IDPMC8758485
Grant ListU01 AG058654 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
RF1-AG057519 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
U01-AG062602 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
R01 AG054672 / AG / NIA NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG032990 / AG / NIA NIH HHS / United States
U19-AG068753 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
U01 AG062602 / AG / NIA NIH HHS / United States
P50 AG025711 / AG / NIA NIH HHS / United States
P01 AG017216 / AG / NIA NIH HHS / United States
R01 AG018023 / AG / NIA NIH HHS / United States
RF1 AG054156 / AG / NIA NIH HHS / United States
RF1 AG054199 / AG / NIA NIH HHS / United States
U01 AG046152 / AG / NIA NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
R01-AG048927 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
HHSN268201500001C / HL / NHLBI NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
R01 AG066429 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01 NS080820 / NS / NINDS NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
R01 AG048927 / AG / NIA NIH HHS / United States
U01 AG046139 / AG / NIA NIH HHS / United States
P01 AG003949 / AG / NIA NIH HHS / United States
75N92019D00031 / HL / NHLBI NIH HHS / United States
RF1 AG057519 / AG / NIA NIH HHS / United States
U01 AG006786 / AG / NIA NIH HHS / United States
U19 AG068753 / AG / NIA NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States

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