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

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 a...

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Bibliographic Details
Published in:Molecular psychiatry 2021-10, Vol.26 (10), p.6054-6064
Main Authors: Panitch, Rebecca, Hu, Junming, Chung, Jaeyoon, Zhu, Congcong, Meng, Gaoyuan, Xia, Weiming, Bennett, David A., Lunetta, Kathryn L., Ikezu, Tsuneya, Au, Rhoda, Stein, Thor D., Farrer, Lindsay A., Jun, Gyungah R.
Format: Article
Language:English
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Alzheimer Disease - genetics
Alzheimer's disease
Apolipoprotein E
Apolipoprotein E2 - genetics
Astrocytes
Behavioral Sciences
Biological Psychology
Brain
C4B protein
Complement C4 - genetics
Gene expression
Gene Expression Profiling
Genotype
Glial stem cells
HSP70 Heat-Shock Proteins - genetics
Humans
Medicine
Medicine & Public Health
Neurodegenerative diseases
Neurosciences
Oligodendrocytes
Pharmacotherapy
Progenitor cells
Psychiatry
Tau protein
Transcriptomes
β-Amyloid
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Summary: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.
ISSN:1359-4184
1476-5578
DOI:10.1038/s41380-021-01266-z