期刊
FRONTIERS IN PHARMACOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.630003
关键词
Alzheimer disease; cytokines; interleukins; microglia; neuroinflammation; toll-like receptors; tumor necrosis factor-alpha; neurodegenerative diseases
资金
- Region Hauts-de-France (Projet Sante Environnement)
- University of Lille
- Centre National de la Recherche Scientifique (Projet Exploratoire Premier Soutien PEPS)
- Lille FHU-VasCog
- Campus France
The study identified 94 proteins significantly associated with neuroinflammation in Alzheimer's disease, with IL4, IL10, and other signaling pathways playing key roles. Key regulators such as IL10 and TLR4 were found to control immune processes, regulated by 63 microRNAs dysregulated in Alzheimer's disease, and targetable by various compounds. This research may help prioritize diagnostic biomarkers and develop effective therapeutic strategies against neuroinflammation in Alzheimer's disease.
Neuroinflammation, as defined by the presence of classically activated microglia, is thought to play a key role in numerous neurodegenerative disorders such as Alzheimer's disease. While modulating neuroinflammation could prove beneficial against neurodegeneration, identifying its most relevant biological processes and pharmacological targets remains highly challenging. In the present study, we combined text-mining, functional enrichment and protein-level functional interaction analyses to 1) identify the proteins significantly associated to neuroinflammation in Alzheimer's disease over the scientific literature, 2) distinguish the key proteins most likely to control the neuroinflammatory processes significantly associated to Alzheimer's disease, 3) identify their regulatory microRNAs among those dysregulated in Alzheimer's disease and 4) assess their pharmacological targetability. 94 proteins were found to be significantly associated to neuroinflammation in Alzheimer's disease over the scientific literature and IL4, IL10 and IL13 signaling as well as TLR-mediated MyD88- and TRAF6-dependent responses were their most significantly enriched biological processes. IL10, TLR4, IL6, AKT1, CRP, IL4, CXCL8, TNF-alpha, ITGAM, CCL2 and NOS3 were identified as the most potent regulators of the functional interaction network formed by these immune processes. These key proteins were indexed to be regulated by 63 microRNAs dysregulated in Alzheimer's disease, 13 long non-coding RNAs and targetable by 55 small molecules and 8 protein-based therapeutics. In conclusion, our study identifies eleven key proteins with the highest ability to control neuroinflammatory processes significantly associated to Alzheimer's disease, as well as pharmacological compounds with single or pleiotropic actions acting on them. As such, it may facilitate the prioritization of diagnostic and target-engagement biomarkers as well as the development of effective therapeutic strategies against neuroinflammation in Alzheimer's disease.
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