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Inflammation as a central mechanism in Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid ? plaques and neurofibrillary tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia-related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms.

SUBMITTER: Kinney JW

PROVIDER: S-EPMC6214864 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Inflammation as a central mechanism in Alzheimer's disease.

Kinney Jefferson W JW Bemiller Shane M SM Murtishaw Andrew S AS Leisgang Amanda M AM Salazar Arnold M AM Lamb Bruce T BT

Alzheimer's & dementia (New York, N. Y.) 20180906

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serv ...[more]

PMID: 30406177

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Project description:ObjectivesNeuroinflammation 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 methodsFrom 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).ResultsOur 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.ConclusionsThe potential core neuroinflammation and associated signaling targets and pathways were identified using integrative network analysis on two large-scale transcriptomics datasets of AD.

Dataset Information

Inflammation as a central mechanism in Alzheimer's disease.

Publications

Inflammation as a central mechanism in Alzheimer's disease.

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