Reduction in GABAB on glia induce Alzheimer's disease related changes.

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JGM, Mice, Animals, Alzheimer Disease, Amyloid beta-Protein Precursor, Neuroinflammatory Diseases, Mice, Transgenic, Amyloid beta-Peptides, Neuroglia, Plaque, Amyloid, gamma-Aminobutyric Acid, Disease Models, Animal

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Brain Behav Immun. 2023;110:260-75







Data collection was sup- ported through funding by NIA (USA) grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNAseq), R01AG17917 (MAP), R01AG36836 (RNAseq), the Illinois Department of Public Health (ROSMAP) (USA), and the Translational Genomics Research Institute (genomic). Data collection was supported through funding by NIA (USA) grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (USA) (U24 NS072026 National Brain and Tissue Resource for Parkin- sons Disease and Related Disorders), the National Institute on Aging (USA) (P30 AG19610 Arizona Alzheimers Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alz- heimers Research Center), the Arizona Biomedical Research Commis- sion (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinsons Research.


Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by beta-amyloid plaques (Aβ), neuro- fibrillary tangles (NFT), and neuroinflammation. Data have demonstrated that neuroinflammation contributes to Aβ and NFT onset and progression, indicating inflammation and glial signaling is vital to understanding AD. A previous investigation demonstrated a significant decrease of the GABAB receptor (GABABR) in APP/PS1 mice (Salazar et al., 2021). To determine if changes in GABABR restricted to glia serve a role in AD, we developed a mouse model with a reduction of GABABR restricted to macrophages, GAB/CX3ert. This model exhibits changes in gene expression and electrophysiological alterations similar to amyloid mouse models of AD. Crossing the GAB/CX3ert mouse with APP/PS1 resulted in significant increases in Aβ pathology. Our data demonstrates that decreased GABABR on macrophages leads to several changes observed in AD mouse models, as well as exacer- bation of AD pathology when crossed with existing models. These data suggest a novel mechanism in AD pathogenesis.