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.
Highlights
Despite extensive research there is still no cure for Alzheimer’s disease, the commonest cause of dementia
Gene Ontology (GO) functional enrichment analyses were performed using ClueGo + CluePedia plug-in to explore the cellular localization, molecular functions and biological pathways associated to these proteins
Molecular function annotations revealed an enrichment for proteins with amyloid-beta or peptide binding activities or cytokine receptor binding activities
Summary
Despite extensive research there is still no cure for Alzheimer’s disease, the commonest cause of dementia. Alzheimer’s disease is characterized by neuronal loss in specific brain regions associated with the formation of amyloid-beta senile plaques and tau-immunoreactive neurofibrillary tangles (Polanco et al, 2018). Another hallmark of the disease is the presence of neuroinflammation as defined by the presence of classically activated microglial cells (Fan et al, 2017; Dani et al, 2018). Microglial cells are the resident immune cells of the central nervous system (Ransohoff and Cardona, 2010) While their activation is needed to defend the brain from injury, it has become clear that a sustained and uncontrolled inflammation could contribute to neurodegeneration, for instance leading to vascular dysfunction, mitochondrial dysfunction and oxidative stress (Sochocka et al, 2013; Orsucci et al, 2013). Mining useful information in these data for the development of diagnostic and therapeutic neuroprotective strategies remains highly challenging
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