Background: Microglia play a critical role in the pathogenesis and development of Alzheimer's disease (AD). Selective small-molecule colony-stimulating factor 1 receptors (CSF1R) inhibitor, designed to deplete microglia, could be used to meliorate AD. This study aimed to investigate the effects and mechanisms of chimeric antigen receptor T (CAR-T) cells targeting CSF1R in 6-month-old APP/PS1 male mice.
Method: The Morris water maze test, Y-maze test, tail suspension test, swimming test, nesting score assay, and three-chamber social interaction assay were performed to assess cognitive function. Western blotting, immunofluorescence staining, enzyme-linked immunosorbent assay, and Bio-Plex Pro Mouse Cytokine 23-plex assays were conducted to explore AD-core pathologies, neuroinflammation, microglial activation and polarization, and pyroptosis.
Result: iCSF1R.CAR-T cells ameliorated cognitive deficits and reduced β-amyloid load, tau hyperphosphorylation, and synapse-related proteins, as well as microglial activation and polarization in 6-month-old APP/PS1 male mice. Furthermore, iCSF1R.CAR-T cells significantly inhibited pyroptosis and attenuated neuroinflammation in these mice.
Conclusion: The results suggest that iCSF1R.CAR-T cells improve cognitive decline and neuroinflammation, possibly by suppressing caspase-1/GSDMD-mediated pyroptosis. Consequently, iCSF1R.CAR-T cells could be a potential therapeutic approach for AD and other neurological disorders characterized by microglial dysfunction.
© 2024 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.