Astrocytes, via RTP801, contribute to cognitive decline by disrupting GABAergic-regulated connectivity and driving...

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.

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.

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.

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.

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.