Astrocytes, via RTP801, contribute to cognitive decline by disrupting GABAergic-regulated connectivity and driving neuroinflammation in an Alzheimer's disease mouse model.

INTRODUCTION: Alzheimer's disease (AD) pathogenesis involves astrocytic responses to extracellular amyloid beta deposits and phospho-tau neurofibrillary tangles, which drive inflammatory activation. RTP801, a stress-responsive protein, has been implicated in mediating neuroinflammation. Its levels are increased in AD hippocampal samples, correlating with disease severity and cognitive decline. METHODS: Using astrocyte-specific RTP801 silencing in the hippocampus of 5xFAD mice, we evaluated cognition, neuroinflammation, and hippocampal connectivity by magnetic resonance spectroscopy (MRS) and resting-state functional connectivity analyses. Histological and biochemical analyses assessed microgliosis, astrogliosis, and inflammasome-related protein levels. RESULTS: Astrocytic RTP801 silencing in 5xFAD mice preserved spatial memory, maintained hippocampal γ-aminobutyric acid (GABA) levels, and preserved resting-state brain networks. In addition, RTP801 silencing significantly reduced markers of microgliosis, astrogliosis, and inflammasome effectors. DISCUSSION: Astrocytic RTP801 contributes to AD-associated cognitive decline by disrupting GABAergic-regulated connectivity and amplifying inflammatory responses. Targeting astrocytic RTP801 may therefore offer therapeutic potential to mitigate AD progression by preserving neural connectivity and reducing neuroinflammation. HIGHLIGHTS: The 5xFAD mouse model of Alzheimer's disease presents higher levels of RTP801 in hippocampal astrocytes. Normalizing the levels of astrocytic RTP801 prevents cognitive decline and restores anxiety-like behavior in the 5xFAD mouse model. Knocking down astrocytic RTP801 preserves the resting-state functional connectivity in the 5xFAD mouse model. Astrocytic RTP801 mediates the loss of Parvalbumin+ interneurons, negatively affecting the levels of γ-aminobutyric acid (GABA) in the 5xFAD mouse model. Astrocytic RTP801 contributes to astro- and microgliosis and inflammasome expression in the 5xFAD mouse model.