Increased cysteinyl-tRNA synthetase drives neuroinflammation in Alzheimer’s disease

Abstract

Background Microglia-mediated neuroinflammation in Alzheimer’s disease (AD) is not only a response to pathophysiological events, but also plays a causative role in neurodegeneration. Cytoplasmic cysteinyl-tRNA synthetase (CARS) is considered to be a stimulant for immune responses to diseases; however, it remains unknown whether CARS is involved in the pathogenesis of AD. Methods Postmortem human temporal cortical tissues at different Braak stages and AD patient-derived serum samples were used to investigate the changes of CARS levels in AD by immunocytochemical staining, real-time PCR, western blotting and ELISA. After that, C57BL/6J and APP/PS1 transgenic mice and BV-2 cell line were used to explore the role of CARS protein in memory and neuroinflammation, as well as the underlying mechanisms. Finally, the associations of morphological features among CARS protein, microglia and dense-core plaques were examined by immunocytochemical staining. Results A positive correlation was found between aging and the intensity of CARS immunoreactivity in the temporal cortex. Both protein and mRNA levels of CARS were increased in the temporal cortex of AD patients. Immunocytochemical staining revealed increased CARS immunoreactivity in neurons of the temporal cortex in AD patients. Moreover, overexpression of CARS in hippocampal neurons induced and aggravated cognitive dysfunction in C57BL/6J and APP/PS1 mice, respectively, accompanied by activation of microglia and the TLR2/MyD88 signaling pathway as well as upregulation of proinflammatory cytokines. In vitro experiments showed that CARS treatment facilitated the production of proinflammatory cytokines and the activation of the TLR2/MyD88 signaling pathway of BV-2 cells. The accumulation of CARS protein occurred within dense-core Aβ plaques accompanied by recruitment of ameboid microglia. Significant upregulation of TLR2/MyD88 proteins was also observed in the temporal cortex of AD. Conclusions The findings suggest that the neuronal CARS drives neuroinflammation and induces memory deficits, which might be involved in the pathogenesis of AD.

Investigating the Neuroprotective and Cognitive-Enhancing Effects of Bacopa monnieri: A Systematic Review Focused on Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis

“…Diseases that induce progressive cognitive and functional impairment, such as Alzheimer's disease, Parkinson's disease, among other related dementias, are among the main contributors to disability and mortality. After the age of 65, the incidence of such pathologies increases exponentially every five years, and after the age of 90, approximately one in three adults meets the criteria for dementia [119][120][121][122][123].…”

Epigenetic modifications of DNA and RNA in Alzheimer’s disease

“…Another tRNA modifying enzyme that may contribute to AD pathogenesis and progression is cytoplasmic cysteinyl-tRNA synthetase (CARS). In APP/PS1 mice and SH-SY5Y neuronal cells, increased CARS expression correlated with AD severity and localized to Aβ plaques, exacerbating memory deficits and inflammatory microglial activation ( Qi et al, 2024 ). Ongoing studies into the functions of tRNA modifications and their modifying enzymes will increase our understanding of their role in AD pathology, neurodegeneration, and age-related diseases.…”