Increased cysteinyl-tRNA synthetase drives neuroinflammation in Alzheimer's disease
Transl Neurodegener. 2024 Jan 8;13(1):3. [ PMID: 38191451 ]
Microglia-driven neuroinflammation is not merely a consequence of Alzheimer's disease (AD) pathology but an active contributor to neurodegeneration. Cytoplasmic cysteinyl-tRNA synthetase (CARS) has been proposed as a stimulant of immune responses, yet its role in AD was unknown. Using postmortem human temporal cortex across Braak stages and AD patient serum, the authors found that CARS protein and mRNA are elevated in AD cortex and that CARS immunoreactivity rises with age. Overexpressing CARS in hippocampal neurons impaired cognition in C57BL/6J mice and worsened deficits in APP/PS1 mice, with microglial activation, TLR2/MyD88 signaling, and proinflammatory cytokines all increased. In vitro, CARS drove cytokine production and TLR2/MyD88 activation in BV-2 microglia. CARS protein accumulated inside dense-core amyloid-beta plaques alongside ameboid microglia, and TLR2/MyD88 were upregulated in AD cortex. The findings implicate neuronal CARS in neuroinflammation and memory deficits, possibly contributing to AD pathogenesis.
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