Astrocytes, via RTP801, contribute to cognitive decline by disrupting GABAergic‐regulated connectivity and driving neuroinflammation in an Alzheimer's disease mouse model
Year: 2025
Type: article
Abstract: 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.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.70051
Institutions: Biomedical Research Networking Center on Neurodegenerative Diseases, Universitat de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, Centro de Investigación Biomédica en Red
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
Funders: Michael J. Fox Foundation for Parkinson's Research, Fundación Ramón Areces, Generalitat de Catalunya, Ministerio de Ciencia e Innovación, Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Universitat de Barcelona, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación
Awards: G1013494351, G1048600441, G1175115578, G1705781321, G1770674688, G1855990336, G1909629148, G2064873908, G2262748287, G2309174360, G2660406951, G2672435700, G288263039, G3005324705, G300979063, G3022609761, G3304279457, G3480869486, G3937122592, G3962952757, G410571670, G4246720701, G425668148, G430777504, G4459426938, G451917667, G4727283876, G5080475149, G5421974903, G5539308778, G5805502524, G5852091828, G5952507127, G5967599077, G7065702806, G7084143925, G8584092977, G8696694383, G8920660035, G99296377
OpenAlex ID: W4410178132