A Computational Exploration of the Molecular Network Associated to Neuroinflammation in Alzheimer’s Disease

Abstract

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.

Nosustrophine: An Epinutraceutical Bioproduct with Effects on DNA Methylation, Histone Acetylation and Sirtuin Expression in Alzheimer’s Disease

“…Inflammation contributes to AD onset and progression [54,55]. Therefore, we next examined the expression of several cytokines and inflammation-related genes in both young (3-4-month-old) and older (8-9-month-old) APP/BIN1/COPS5 and wild-type mice.…”

Associations Between Oral Health Status, Perceived Stress, and Neuropsychiatric Symptoms Among Community Individuals With Alzheimer's Disease: A Mediation Analysis

“…The genetic and environmental risk factors associated with the onset and progression of AD are heterogeneous and sporadic. Emerging evidence suggests a link between AD and oral health, based on self-reported oral health-related quality of life (OHRQoL), objective indicators of oral health clinical assessments (e.g., missing teeth and gingival bleeding) (Ericsson et al, 2009 ; Zuluaga et al, 2012 ), and other indicators, including oral microbiota (Sureda et al, 2020 ), active potent neuroinflammatory regulators (e.g., IL-1β, IL-6, and TNF-α) (El Idrissi et al, 2021 ), and high salivary cortisol levels (Venturelli et al, 2016 ). An age-related change of oral status together with a decline in cognitive may be defined as a state of oral frailty (Dibello et al, 2021 ), representing toothache, oral dryness, tooth loss, dental caries, periodontal disease, and a set of worse oral daily practice functions, which may result in psychological distress (Vasiliou et al, 2016 ; Turner et al, 2017 )and behavioral disturbances (Park et al, 2014 ; Kubo et al, 2017 ; Dahl et al, 2018 ).…”

Serum metabolomics analysis combined with network pharmacology reveals possible mechanisms of postoperative cognitive dysfunction in the treatment of Mongolian medicine Eerdun Wurile basic formula

“…Studies have shown that the incidence of POCD in people aged over 65 years ranges from 9% to 54% at 1 week postoperatively (Androsova et al, 2015), and the incidence of POCD has increased with the aging of the population in recent years (Zhang et al, 2021). The pathogenesis of POCD is unknown, but studies suggest that it is related to the neurotransmitter theory (Rivero‐Segura et al, 2019), the brain injury theory (Wiberg et al, 2022), and the neuroinflammatory theory (El Idrissi et al, 2021). At present, there are no satisfactory drugs for the treatment and prevention of POCD, except for dexmedetomidine hydrochloride and ustekin, which are given in the perioperative period.…”

“…studies suggest that it is related to the neurotransmitter theory (Rivero-Segura et al, 2019), the brain injury theory (Wiberg et al, 2022), and the neuroinflammatory theory (El Idrissi et al, 2021).…”