Novel Microglia-based Therapeutic Approaches to Neurodegenerative Disorders

Zhang, Lijuan; Liu, Taohui; Mao, Ying; Peng, Bo

doi:10.1007/s12264-022-01013-6

Cited by 23 publications

(14 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Microglia are closely related to the cognitive impairment and pathology of AD [ 46 , 47 ]. To investigate the potential mechanism of CARS-induced memory impairment, we examined the effects of neuronal CARS overexpression on microglia in the hippocampus of the C57BL/6J mice.…”

Section: Resultsmentioning

confidence: 99%

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

Qi,

Chen,

Wang

et al. 2024

Transl Neurodegener

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

Qi,

Chen,

Wang

et al. 2024

Transl Neurodegener

View full text Add to dashboard Cite

show abstract

“…Previous research has primarily focused on investigating the involvement of immune cells, particularly microglia, the resident macrophages of the CNS, in the pathogenesis of AD. Numerous studies have extensively examined and confirmed the characteristics of aging microglia ( 26 ), their role in the development of AD ( 27 ), and the effectiveness of interventions targeting aging microglia ( 28 ). However, it is important to recognize that AD is systemically influenced by both central and peripheral factors.…”

Section: Discussionmentioning

confidence: 99%

Rejuvenation of peripheral immune cells attenuates Alzheimer’s disease-like pathologies and behavioral deficits in a mouse model

Sun,

Liu,

et al. 2024

Sci. Adv.

View full text Add to dashboard Cite

Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer’s disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aβ plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aβ clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

show abstract

“…Recent studies verified this therapeutic effect of Mr BMT in an AD mouse model (87, 88), demonstrating the clinical potential of microglia replacement. It also provides new and clinically feasible strategies for treating other neurological disorders (18, 85, 86, 89). Despite sharing similar characteristics with naïve microglia, Mr BMT cells are P2Y12 − (18).…”

Section: Discussionmentioning

confidence: 99%

Microglia facilitate and stabilize the response to general anesthesia

He,

Liu,

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

General anesthesia leads to a loss of consciousness and an unarousable state in patients. Although general anesthetics are widely used in clinical practice, their underlying mechanisms remain elusive. The potential involvement of nonneuronal cells is unknown. Microglia are important immune cells in the central nervous system (CNS) that play critical roles in CNS function and dysfunction. We unintentionally observed delayed anesthesia induction and early anesthesia emergence in microglia-depleted mice. We found that microglial depletion differentially regulates neuronal activities by suppressing the neuronal network of anesthesia-activated brain regions and activating emergence-activated brain regions. Thus, microglia facilitate and stabilize the anesthesia status. This influence is not mediated by dendritic spine plasticity. Instead, it relies on the activation of microglial P2Y12 and subsequent calcium influx, which facilitates the general anesthesia response. Together, we elucidate the regulatory role of microglia in general anesthesia, extending our knowledge of how nonneuronal cells modulate neuronal activities.

show abstract

Novel Microglia-based Therapeutic Approaches to Neurodegenerative Disorders

Cited by 23 publications

References 109 publications

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

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

Rejuvenation of peripheral immune cells attenuates Alzheimer’s disease-like pathologies and behavioral deficits in a mouse model

Microglia facilitate and stabilize the response to general anesthesia

Contact Info

Product

Resources

About