TY - JOUR
T1 - Weakly activated core neuroinflammation pathways were identified as a central signaling mechanism contributing to the chronic neurodegeneration in Alzheimer’s disease
AU - Li, Fuhai
AU - Eteleeb, Abdallah M.
AU - Buchser, William
AU - Sohn, Christopher
AU - Wang, Guoqiao
AU - Xiong, Chengjie
AU - Payne, Philip R.
AU - McDade, Eric
AU - Karch, Celeste M.
AU - Harari, Oscar
AU - Cruchaga, Carlos
N1 - Funding Information:
This work was partially supported by the National Institute of Ageing (NIA) R56AG065352 to Dr. Li. We thank all the participants and their families, as well as the many involved institutions and their staff, grants from the National Institutes of Health [R01AG044546 (CC), P01AG003991 (CC), RF1AG053303 (CC), RF1AG058501 (CC), and U01AG058922 (CC)] and Chuck Zuckerberg Initiative (CZI), access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine. CC receives research support from: Biogen, EISAI, Alector, and Parabon. CC was a member of the advisory board of Vivid Genomics, Halia Therapeutics, and ADx Healthcare.
Funding Information:
This work was partially supported by the National Institute of Ageing (NIA) R56AG065352 to Dr. Li. We thank all the participants and their families, as well as the many involved institutions and their staff, grants from the National Institutes of Health [R01AG044546 (CC), P01AG003991 (CC), RF1AG053303 (CC), RF1AG058501 (CC), and U01AG058922 (CC)] and Chuck Zuckerberg Initiative (CZI), access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine. CC receives research support from: Biogen, EISAI, Alector, and Parabon. CC was a member of the advisory board of Vivid Genomics, Halia Therapeutics, and ADx Healthcare.
Publisher Copyright:
Copyright © 2022 Li, Eteleeb, Buchser, Sohn, Wang, Xiong, Payne, McDade, Karch, Harari and Cruchaga.
PY - 2022/9/27
Y1 - 2022/9/27
N2 - Objectives: Neuroinflammation signaling has been identified as an important hallmark of Alzheimer’s disease (AD) in addition to amyloid β plaques (Aβ) and neurofibrillary tangles (NFTs). However, the molecular mechanisms and biological processes of neuroinflammation remain unclear and have not well delineated using transcriptomics data available. Our objectives are to uncover the core neuroinflammation signaling pathways in AD using integrative network analysis on the transcriptomics data. Materials and methods: From a novel perspective, i.e., investigating weakly activated molecular signals (rather than the strongly activated molecular signals), we developed integrative and systems biology network analysis to uncover potential core neuroinflammation signaling targets and pathways in AD using the two large-scale transcriptomics datasets, i.e., Mayo Clinic (77 controls and 81 AD samples) and ROSMAP (97 controls and 260 AD samples). Results: Our analysis identified interesting core neuroinflammation signaling pathways, which are not systematically reported in the previous studies of AD. Specifically, we identified 7 categories of signaling pathways implicated on AD and related to virus infection: immune response, x-core signaling, apoptosis, lipid dysfunctional, biosynthesis and metabolism, and mineral absorption signaling pathways. More interestingly, most of the genes in the virus infection, immune response, and x-core signaling pathways are associated with inflammation molecular functions. The x-core signaling pathways were defined as a group of 9 signaling proteins: MAPK, Rap1, NF-kappa B, HIF-1, PI3K-Akt, Wnt, TGF-beta, Hippo, and TNF, which indicated the core neuroinflammation signaling pathways responding to the low-level and weakly activated inflammation and hypoxia and leading to the chronic neurodegeneration. It is interesting to investigate the detailed signaling cascades of these weakly activated neuroinflammation signaling pathways causing neurodegeneration in a chronic process, and consequently uncover novel therapeutic targets for effective AD treatment and prevention. Conclusions: The potential core neuroinflammation and associated signaling targets and pathways were identified using integrative network analysis on two large-scale transcriptomics datasets of AD.
AB - Objectives: Neuroinflammation signaling has been identified as an important hallmark of Alzheimer’s disease (AD) in addition to amyloid β plaques (Aβ) and neurofibrillary tangles (NFTs). However, the molecular mechanisms and biological processes of neuroinflammation remain unclear and have not well delineated using transcriptomics data available. Our objectives are to uncover the core neuroinflammation signaling pathways in AD using integrative network analysis on the transcriptomics data. Materials and methods: From a novel perspective, i.e., investigating weakly activated molecular signals (rather than the strongly activated molecular signals), we developed integrative and systems biology network analysis to uncover potential core neuroinflammation signaling targets and pathways in AD using the two large-scale transcriptomics datasets, i.e., Mayo Clinic (77 controls and 81 AD samples) and ROSMAP (97 controls and 260 AD samples). Results: Our analysis identified interesting core neuroinflammation signaling pathways, which are not systematically reported in the previous studies of AD. Specifically, we identified 7 categories of signaling pathways implicated on AD and related to virus infection: immune response, x-core signaling, apoptosis, lipid dysfunctional, biosynthesis and metabolism, and mineral absorption signaling pathways. More interestingly, most of the genes in the virus infection, immune response, and x-core signaling pathways are associated with inflammation molecular functions. The x-core signaling pathways were defined as a group of 9 signaling proteins: MAPK, Rap1, NF-kappa B, HIF-1, PI3K-Akt, Wnt, TGF-beta, Hippo, and TNF, which indicated the core neuroinflammation signaling pathways responding to the low-level and weakly activated inflammation and hypoxia and leading to the chronic neurodegeneration. It is interesting to investigate the detailed signaling cascades of these weakly activated neuroinflammation signaling pathways causing neurodegeneration in a chronic process, and consequently uncover novel therapeutic targets for effective AD treatment and prevention. Conclusions: The potential core neuroinflammation and associated signaling targets and pathways were identified using integrative network analysis on two large-scale transcriptomics datasets of AD.
KW - Alzheimer’s disease
KW - molecular mechanism
KW - neuroinflammation
KW - signaling network
KW - signaling targets
UR - http://www.scopus.com/inward/record.url?scp=85139564627&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85139564627&partnerID=8YFLogxK
U2 - 10.3389/fnagi.2022.935279
DO - 10.3389/fnagi.2022.935279
M3 - Article
C2 - 36238934
AN - SCOPUS:85139564627
SN - 1663-4365
VL - 14
SP - 935279
JO - Frontiers in Aging Neuroscience
JF - Frontiers in Aging Neuroscience
M1 - 935279
ER -