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

May 7, 2025Alzheimer's & dementia : the journal of the Alzheimer's Association

Astrocytes may cause memory loss in Alzheimer's mice by disrupting inhibitory brain connections and increasing brain inflammation through RTP801

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Abstract

Astrocytic silencing in 5xFAD mice preserved spatial memory and maintained hippocampal GABA levels.

Silencing RTP801 significantly reduced markers of microgliosis and astrogliosis.
Levels of RTP801 are increased in hippocampal astrocytes from 5xFAD mice, correlating with cognitive decline.
Disruption of GABAergic connectivity is linked to astrocytic RTP801's role in cognitive decline associated with Alzheimer's disease.
Resting-state functional connectivity was preserved after RTP801 silencing in the .
Targeting astrocytic RTP801 could potentially mitigate Alzheimer's disease progression.

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INTRODUCTION: Alzheimer's disease (AD) pathogenesis involves astrocytic responses to extracellular amyloid beta deposits and phospho-tau neurofibrillary tangles, which drive inflammatory activation. , 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 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.

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30%

Decrease in astrocytic levels

Astrocytic levels decreased after silencing in CA1 and DG regions.

6 days

Cognitive improvement in 5xFAD mice

5xFAD miRTP801 mice showed significant improvement in Morris water maze performance over 6 days.

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

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