TDP-43 pathology triggers neuroinflammation and cognitive impairment by inducing microglial necroptosis

ABSTRACT: Pathological TAR DNA-binding protein-43 (TDP-43) is a defining feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). However, the mechanism by which TDP-43 pathology disrupts microglial function and drives neuroinflammation remain unclear. In this study, we demonstrated that cytoplasmic mis-localized TDP-43 exacerbated neuroinflammation, induced cell death, and impaired phagocytic function in microglial cells, primarily through receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis. Pharmacological inhibition of RIPK3 with GSK872 markedly attenuated these pathological effects in vitro. These findings were further corroborated in a murine model with cytoplasmic TDP-43 mi

SUBMITTER: Shenrui Guo 

PROVIDER: S-SCDT-10_1038-S44321-026-00394-9 | biostudies-other |

REPOSITORIES: biostudies-other