Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders DOI Creative Commons
Yige Huang,

Bangyan Liu,

Subhash C. Sinha

et al.

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Nov. 8, 2023

Abstract DNA sensing is a pivotal component of the innate immune system that responsible for detecting mislocalized and triggering downstream inflammatory pathways. Among sensors, cyclic GMP-AMP synthase (cGAS) primary player in cytosolic DNA, including foreign from pathogens self-DNA released during cellular damage, culminating type I interferon (IFN-I) response through stimulator genes (STING) activation. IFN-I cytokines are essential mediating neuroinflammation, which widely observed CNS injury, neurodegeneration, aging, suggesting an upstream role cGAS pathway. In this review, we summarize latest developments on cGAS-STING DNA-driven various neurological diseases conditions. Our review covers current understanding molecular mechanisms activation highlights signaling cell types central peripheral nervous systems, such as resident brain cells, neurons, glial cells. We then discuss different neurodegenerative conditions, tauopathies, Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis, well aging senescence. Finally, lay out advancements research development inhibitors assess prospects targeting STING therapeutic strategies wide spectrum diseases.

Language: Английский

Microglia use TAM receptors to detect and engulf amyloid β plaques DOI
Youtong Huang, Kaisa E. Happonen,

Patrick Burrola

et al.

Nature Immunology, Journal Year: 2021, Volume and Issue: 22(5), P. 586 - 594

Published: April 15, 2021

Language: Английский

Citations

326
Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology DOI Creative Commons
Seung-Hye Lee, William J. Meilandt, Luke Xie

et al.

Neuron, Journal Year: 2021, Volume and Issue: 109(8), P. 1283 - 1301.e6

Published: March 7, 2021

Language: Английский

Citations

190
Role of the cGAS–STING pathway in systemic and organ-specific diseases DOI Open Access
Sladjana Skopelja‐Gardner, Jie An, Keith B. Elkon

et al.

Nature Reviews Nephrology, Journal Year: 2022, Volume and Issue: 18(9), P. 558 - 572

Published: June 22, 2022

Language: Английский

Citations

180
Emerging roles of innate and adaptive immunity in Alzheimer’s disease DOI Creative Commons
Xiaoying Chen, David M. Holtzman

Immunity, Journal Year: 2022, Volume and Issue: 55(12), P. 2236 - 2254

Published: Nov. 8, 2022

Language: Английский

Citations

176
A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites DOI Creative Commons
Hongli Shi, Xing Ge, Xi Ma

et al.

Microbiome, Journal Year: 2021, Volume and Issue: 9(1)

Published: Nov. 11, 2021

Abstract Background Cognitive impairment, an increasing mental health issue, is a core feature of the aging brain and neurodegenerative diseases. Industrialized nations especially, have experienced marked decrease in dietary fiber intake, but potential mechanism linking low intake cognitive impairment poorly understood. Emerging research reported that diversity gut microbiota Western populations significantly reduced. However, it unknown whether fiber-deficient diet (which alters microbiota) could impair cognition functional elements through gut-brain axis. Results In this study, mouse model long-term (15 weeks) deficiency (FD) was used to mimic sustained humans. We found FD mice showed impaired cognition, including deficits object location memory, temporal order ability perform daily living activities. The hippocampal synaptic ultrastructure damaged mice, characterized by widened clefts thinned postsynaptic densities. A proteomic analysis further identified deficit CaMKIId its associated proteins (including GAP43 SV2C) along with neuroinflammation microglial engulfment synapses. also exhibited dysbiosis (decreased Bacteroidetes increased Proteobacteria), which deficits. Of note, rapid differentiating change observed short-term (7 days) before highlighting possible causal impact profile on outcomes. Moreover, compromised intestinal barrier reduced short-chain fatty acid (SCFA) production. exploit these findings for SCFA receptor knockout oral supplementation verified playing critical role altered impairment. Conclusions This first time, reports fiber-deprived leads altering microbiota-hippocampal axis, pathologically distinct from normal aging. These alert adverse function, highlight increase as nutritional strategy reduce risk developing diet-associated decline

Language: Английский

Citations

161
Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease DOI Creative Commons
Y. Rajesh, Thirumala‐Devi Kanneganti

Cells, Journal Year: 2022, Volume and Issue: 11(12), P. 1885 - 1885

Published: June 10, 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder molecularly characterized by the formation of amyloid β (Aβ) plaques and type 2 microtubule-associated protein (Tau) abnormalities. Multiple studies have shown that many brain’s immunological cells, specifically microglia astrocytes, are involved in AD pathogenesis. Cells innate immune system play an essential role eliminating pathogens but also regulate brain homeostasis AD. When activated, cells can cause programmed cell death through multiple pathways, including pyroptosis, apoptosis, necroptosis, PANoptosis. The often results release proinflammatory cytokines propagate response eliminate Aβ aggregated Tau proteins. However, chronic neuroinflammation, which result from death, has been linked to diseases worsen Therefore, must be tightly balanced appropriately clear these AD-related structural abnormalities without inducing neuroinflammation. In this review, we discuss responses, inflammatory cytokine secretion as they relate Therapeutic strategies targeting mechanisms will critical consider for future preventive or palliative treatments

Language: Английский

Citations

155
COVID-19-Associated Neurological Disorders: The Potential Route of CNS Invasion and Blood-Brain Barrier Relevance DOI Creative Commons

Aneesha Achar,

Chaitali Ghosh

Cells, Journal Year: 2020, Volume and Issue: 9(11), P. 2360 - 2360

Published: Oct. 27, 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human that has sparked global pandemic of the disease 2019 (COVID-19). The virus invades cells through angiotensin-converting enzyme (ACE2) receptor-driven pathway, primarily targeting tract. However, emerging reports neurological manifestations demonstrate neuroinvasive potential SARS-CoV-2. This review highlights possible routes by which SARS-CoV-2 may invade central nervous system (CNS) and provides insight into recent case COVID-19-associated disorders, namely ischaemic stroke, encephalitis, encephalopathy, epilepsy, neurodegenerative diseases, inflammatory-mediated disorders. We hypothesize neuroinvasion, neuroinflammation, blood-brain barrier (BBB) dysfunction be implicated in development observed disorders; however, further research critical to understand detailed mechanisms pathway infectivity behind CNS pathogenesis.

Language: Английский

Citations

151
Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience DOI Creative Commons
Joe C. Udeochu, Sadaf Amin, Yige Huang

et al.

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(5), P. 737 - 750

Published: April 24, 2023

Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period cognitive resilience before the onset dementia. Here, we report that activation cyclic GMP-AMP synthase (cGAS) diminishes decreasing neuronal transcriptional network myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, part mediated cytosolic leakage mitochondrial DNA. Genetic ablation Cgas mice with tauopathy diminished microglial response, preserved synapse integrity plasticity protected against impairment without affecting pathogenic load. increased, while decreased, MEF2C expression linked to AD. Pharmacological inhibition enhanced restored synaptic integrity, memory, supporting therapeutic potential targeting cGAS-IFN-MEF2C axis improve AD-related pathological insults.

Language: Английский

Citations

149
Hyperinflammatory Immune Response and COVID-19: A Double Edged Sword DOI Creative Commons

Li Yin Tan,

Thamil Vaani Komarasamy, Vinod Balasubramaniam

et al.

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Sept. 30, 2021

The coronavirus disease-19 (COVID-19) elicited by the severe acute respiratory syndrome 2 (SARS-CoV-2) has caused devastating health, economic and social impact worldwide. Its clinical spectrum ranges from asymptomatic to failure multi-organ or death. pathogenesis of SARS-CoV-2 infection is attributed a complex interplay between virus host immune response. It involves activation multiple inflammatory pathways leading hyperinflammation cytokine storm, resulting in tissue damage, distress (ARDS) failure. Accumulating evidence raised concern over long-term health effects COVID-19. Importantly, neuroinvasive potential may have consequences brain. This review provides conceptual framework on how tricks system induce cause disease. We also explore key differences mild COVID-19 its short- effects, particularly human

Language: Английский

Citations

142
Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques DOI Creative Commons
Ethan R. Roy,

Gabriel S. Chiu,

Sanming Li

et al.

Immunity, Journal Year: 2022, Volume and Issue: 55(5), P. 879 - 894.e6

Published: April 19, 2022

Language: Английский

Citations

138