Cargando…
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 amo...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8758485/ https://www.ncbi.nlm.nih.gov/pubmed/34480088 http://dx.doi.org/10.1038/s41380-021-01266-z |
_version_ | 1784632914696208384 |
---|---|
author | 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. |
author_facet | 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. |
author_sort | Panitch, Rebecca |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8758485 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-87584852022-01-26 Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease 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. Mol Psychiatry Article 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. Nature Publishing Group UK 2021-09-03 2021 /pmc/articles/PMC8758485/ /pubmed/34480088 http://dx.doi.org/10.1038/s41380-021-01266-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article 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. Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease |
title | Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease |
title_full | Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease |
title_fullStr | Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease |
title_full_unstemmed | Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease |
title_short | Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease |
title_sort | integrative brain transcriptome analysis links complement component 4 and hspa2 to the apoe ε2 protective effect in alzheimer disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8758485/ https://www.ncbi.nlm.nih.gov/pubmed/34480088 http://dx.doi.org/10.1038/s41380-021-01266-z |
work_keys_str_mv | AT panitchrebecca integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease AT hujunming integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease AT chungjaeyoon integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease AT zhucongcong integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease AT menggaoyuan integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease AT xiaweiming integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease AT bennettdavida integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease AT lunettakathrynl integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease AT ikezutsuneya integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease AT aurhoda integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease AT steinthord integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease AT farrerlindsaya integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease AT jungyungahr integrativebraintranscriptomeanalysislinkscomplementcomponent4andhspa2totheapoee2protectiveeffectinalzheimerdisease |