Title | Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Panitch 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 |
Journal | Mol Psychiatry |
Volume | 26 |
Issue | 10 |
Pagination | 6054-6064 |
Date Published | 2021 Oct |
ISSN | 1476-5578 |
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. |
DOI | 10.1038/s41380-021-01266-z |
Pubmed Link | https://www.ncbi.nlm.nih.gov/pubmed/34480088?dopt=Abstract |
page_expo | External |
Alternate Journal | Mol Psychiatry |
PubMed ID | 34480088 |
PubMed Central ID | PMC8758485 |
Grant List | U01 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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