Lipid metabolism transcriptomics of murine microglia in Alzheimer’s disease and neuroinflammation

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques followed by intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. An unrestrained immune response by microglia, the resident cells of the central nervous system (CNS), leads to neuroinflammation which can amplify AD pathology. AD pathology is also driven by metabolic dysfunction with strong correlations between dementia and metabolic disorders such as diabetes, hypercholesterolemia, and hypertriglyceridemia. Since elevated cholesterol and triglyceride levels appear to be a major risk factor for developing AD, we investigated the lipid metabolism transcriptome in an AD versus non-AD state using RNA-sequencing (RNA-seq) and microarray datasets from N9 cells and murine microglia. We identified 52 differentially expressed genes (DEG) linked to lipid metabolism in LPS-stimulated N9 microglia versus unstimulated control cells using RNA-seq, 86 lipid metabolism DEG in 5XFAD versus wild-type mice by microarray, with 16 DEG common between both datasets. Functional enrichment and network analyses identified several biological processes and molecular functions, such as cholesterol homeostasis, insulin signaling, and triglyceride metabolism. Furthermore, therapeutic drugs targeting lipid metabolism DEG found in our study were identified. Focusing on drugs that target genes associated with lipid metabolism and neuroinflammation could provide new targets for AD drug development.

AIBP controls TLR4 inflammarafts and mitochondrial dysfunction in a mouse model of Alzheimer’s disease

“…Aβ oligomers and other DAMPs engage inflammatory receptors located in lipid rafts and induce fusion of isolated lipid rafts into inflammarafts enriched with TLR4 dimers and likely other receptor complexes. These processes initiate cell reprogramming, including alterations in cholesterol and lipid metabolism, which help maintain high levels of cholesterol, sphingolipids and phospholipids with long saturated fatty acyl chains – all the components of lipid rafts 5, 7, 25 . The exact genetic, epigenetic and metabolic mechanisms of chronic TLR4 inflammaraft maintenance in microglia exposed to Aβ remain to be elucidated.…”

Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer’s Disease

“…Daily administration of an insulin-sensitizing compound ameliorated female-specific metabolic imbalances in a mouse model of AD [316]. Whether using drugs targeting genes associated with both lipid metabolism and neuroinflammation [317] will be efficacious in one or both sexes, if at all, remains to be determined.…”

In vitro biological studies and computational prediction-based analyses of pyrazolo[1,5-a]pyrimidine derivatives

“…Based on the scientic truths mentioned above about antioxidant agents, diabetes mellitus, Alzheimer's disease, cancer, disease statistics in the Arab world, and therapeutic strategies, the bioactive pyrazolo[1,5-a]pyrimidine and its drug derivatives as well as the continuation of our target of synthesizing bioactive nitrogenous derivatives, [42][43][44] in addition to the concept of multi-target drugs, [45][46][47][48][49][50][51] and the relationship between diverse diseases. [52][53][54] Accordingly, in this work, we selected the two pyrazolo[1,5-a]pyrimidines 12a and 12b, which possess pharmacology activities against MCF-7 and HepG-2 cell lines, respectively, 55 and possess promising antimicrobial and immunomodulatory activities 56 for evaluating of their biological potentials as antioxidant, anti-diabetic, anti-Alzheimer, antiarthritic, and anticancer agents. Finally, computational prediction-based analyses were performed (Fig.…”