Integrative Computational Network Analysis Reveals Site-Specific Mediators of Inflammation in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a major neurodegenerative disease and is one of the most common cause of dementia in older adults. Among several factors, neuroinflammation is known to play a critical role in the pathogenesis of chronic neurodegenerative diseases. In particular, studies of brains affected by AD show a clear involvement of several inflammatory pathways. Furthermore, depending on the brain regions affected by the disease, the nature and the effect of inflammation can vary. Here, in order to shed more light on distinct and common features of inflammation in different brain regions affected by AD, we employed a computational approach to analyze gene expression data of six site-specific neuronal populations from AD patients. Our network based computational approach is driven by the concept that a sustained inflammatory environment could result in neurotoxicity leading to the disease. Thus, our method aims to infer intracellular signaling pathways/networks that are likely to be constantly activated or inhibited due to persistent inflammatory conditions. The computational analysis identified several inflammatory mediators, such as tumor necrosis factor alpha (TNF-a)-associated pathway, as key upstream receptors/ligands that are likely to transmit sustained inflammatory signals. Further, the analysis revealed that several inflammatory mediators were mainly region specific with few commonalities across different brain regions. Taken together, our results show that our integrative approach aids identification of inflammation-related signaling pathways that could be responsible for the onset or the progression of AD and can be applied to study other neurodegenerative diseases. Furthermore, such computational approaches can enable the translation of clinical omics data toward the development of novel therapeutic strategies for neurodegenerative diseases.

Receptors for pro‐resolving mediators are increased in Alzheimer's disease brain

“…In addition, BF neurons also send projections to the CG (13), and a study revealed that enhancing cholinergic signaling by ACh esterase inhibitor treatment resulted in restoration of cerebral blood flow in the posterior CG, concomitant with improved cognitive function in AD patients (38). A recent study showed an increase in the levels of TNF receptor 1 (TNFR1) in the posterior CG of patients with AD (63), which together with our present results on HLA-DR show an inflammatory profile in AD also in this part of the limbic system.…”

Ameliorative effects and possible molecular mechanisms of action of fibrauretine fromFibraurea recisaPierre ond-galactose/AlCl3-mediated Alzheimer's disease

“…Numerous studies demonstrated that neuroinflammation plays a critical role in the pathogenesis of AD, showing a clear involvement of several inflammatory pathways. 49 NF-κB is a pro-inflammatory transcription factor located in the cytoplasm via binding to the inhibitory IκB protein. IκB is degraded by the proteasome when it is stimulated by pathogens.…”