Metabolic reprogramming in inflammatory microglia indicates a potential way of targeting inflammation in Alzheimer's disease

• DOI: 10.1016/j.redox.2023.102846
• Publication Date: 2023-08-09T16:25:55Z
• Authors: Moris Sangineto; Martina Ciarnelli; Tommaso Cassano; Antonio Radesco; Archana Moola; Vidyasagar Naik B...; Antonino Romano; Rosanna Villani; Hina Kanwal; Nazzareno Capitanio; Loren Duda; Carlo Avolio; Gaetano Serviddio
• Keywords: Lipopolysaccharides; Inflammation; Medicine (General); Immunometabolism; Macrophage; QH301-705.5; 610; Mice, Transgenic; Alzheimer's disease; Bioenergetics; 3. Good health; Toll-Like Receptor 4; Mice; R5-920; Alzheimer Disease; Animals; Microglia; Biology (General); Dimethyl malonate; Research Paper

Microglia activation drives the pro-inflammatory activity in early stages of Alzheimer's disease (AD). However, mechanistic basis is elusive, and hypothesis targeting microglia to prevent AD onset little explored. Here, we demonstrated that upon LPS exposure, shift towards an energetic phenotype characterised by high glycolysis mitochondrial respiration with dysfunction. Although electron transport chain (ETC) complexes boosted LPS, this mostly devoted generation reactive oxygen species. We showed inhibiting succinate dehydrogenase (SDH) dimethyl malonate (DMM), it possible modulate LPS-induced metabolic rewiring, facilitating anti-inflammatory phenotype. DMM improves function a direct way reducing biogenesis. Moreover, block SDH inhibits recruitment hypoxia inducible-factor 1 α (HIF-1α), which mediates induction cytokine expression. Similar bioenergetic alterations were observed isolated from mice (3xTg-AD), present levels circulating brain toll-like receptor4 (TLR4). well-established model was used show potential effect inhibition vivo as administration abrogated inflammation modulated 3xTg-AD mice. The RNA-sequencing analysis public dataset confirmed consistent transcription genes encoding for ETC subunits (5xFAD). In conclusion, TLR4 promotes changes microglia, might represent promising therapeutic target development.