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iNature
CICL GMP SATASE (CGAS) DETECTS MICROBIAL AND HOST-DERIVED DOUBLE-STRANDED DNA IN THE CYTOPLASM TO TRIGGER CELLULAR INNATE IMMUNE RESPONSES
IN A STIMULATOR OF INTERFERON GENES (STING)-DEPENDENT MANNER.
However, whether the cGAS-STING pathway in innate immunity contributes to Alzheimer's disease (AD) is unclear
.
On January 9, 2023, Zeng Jianxiong's research group at the Kunming Institute of Zoology, Chinese Academy of Sciences, and Zhen Zhao's research group at the University of Southern California, published an online report entitled "Activation of innate immune cGAS-STING pathway contributes to Alzheimer's pathogenesis in 5× in the journal Nature Aging FAD mice" research paper
.
The study detected cytoplasmic binding of cGAS to dsDNA and subsequent activation
of the cGAS-sting pathway in the brains of human AD and aged mice.
In the 5′FAD mouse model, both hereditary Cgas deficiency and STING inhibitors alleviated the pathogenesis of AD, which may be partly due to the inhibition
of neurotoxic A1 astrocytes.
These findings are consistent with
the idea that innate immunity plays a key role in the pathogenesis and progression of AD.
Together, this study has identified key molecular links between innate immunity and AD and suggests that therapeutic targeting of cGAS-STING pathway activity may effectively interfere with the progression of
AD.
many organisms.
In mammalian cells, this process is primarily mediated by the circulating GMP-AMP synthase (cGAS)-interferon gene stimulating factor (STING) pathway, which is a mechanistic coupling
between DNA sensing and triggering of effective innate immune defense programs.
In this pathway, cGAS binds to double-stranded DNA (dsDNA), allosteric activates its catalytic activity, and produces 2'3' loop GMP-AMP (2'3'-cGAMP), a second messenger molecule, and a potent agonist
of STING2-6.
ACTIVATED STING RECRUITS TANK-BINDING KINASE 1 (TBK1), WHICH CAN PHOSPHORYLATE STING AND THE TRANSCRIPTION FACTOR INTERFERON REGULATOR 3 (IRF3).
Phosphorylation of IRF3 leads to its dimerization and translocation into the nucleus, where phosphorylated IRF3 and nuclear factor κB (NF-κB), the latter is a transcription factor that is also activated by STING, working together to initiate the expression of type I interferons (IFNs) and inflammatory factors, triggering a broad immune response
.
However, the cGAS-sting pathway plays a biological role beyond antimicrobial defense, as cGAS senses and binds dsDNA
in a sequence-independent way.
cGAS can be activated
by cytoplasmic auto-DNA derived from genomic or mitochondrial DNA (mtDNA).
There is growing evidence that the cGAS-STING pathway plays an increasingly important role in a variety of physiological and pathological processes, including host defense against microbial infection, anti-tumor immunity, cellular senescence, autophagy, autoimmune, and inflammatory diseases
.
Recent studies have shown that the cGAS-STING pathway is involved in neurological disorders such as ischemic brain injury, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis
.
In these diseases, acute or chronic neuroinflammatory responses induced by the cGAS-STING pathway contribute to the pathological progression
of the disease.
In particular, in tau pathology in Alzheimer's disease (AD), the most common neurodegenerative disease, the microglial cGAS-STING pathway may play an important role
in brain inflammation.
However, whether and how the innate immune cGAS-STING pathway is involved in the development and progression of amyloid pathology in AD is unclear
.
AD is characterized by the accumulation of amyloid β (Aβ) in plaques, overphosphorylated tau aggregation in nerve fiber tangles, and neuroinflammation, which together lead to neurodegeneration and cognitive decline
.
Neurodegenerative proteins such as Aβ can cause oxidative damage to mitochondrial DNA and DNA double-strand breaks (dsb) in neuronal cultures, which may increase cytoplasmic dsDNA28 levels
.
cGAS and STING are mainly expressed in microglia, resident immune cells of the central nervous system (CNS), so the type I IFNs and inflammatory responses induced by the cGAS-STING pathway are potent in microglia and weaker
in neurons and astrocytes under viral infection conditions.
In this study, the researchers demonstrated detectable binding of cGAS double-stranded DNA and activation of the microglial cGAS-STING pathway in the cytoplasm in the brains of human AD and aged mice
.
Cgas−/−; 5×FAD mice are largely protected from cognitive impairment, amyloid-β pathology, neuroinflammation, and other AD-related sequelae
.
In addition, microglia lack of Cgas inhibits the neurotoxic A1 astrocyte phenotype, thereby mitigating amyloid oligo-β peptide-induced neurotoxicity
.
Finally, the administration of STING inhibitor H-151 effectively inhibited the activation of the cGAS-STING pathway in 5×FAD mice and improved the pathogenesis
of AD.
Administration of STING inhibitor H-151 improves Aβ pathology and neuroinflammation in mice 5 ́FAD (Image from Nature Aging) Overall, this study revealed the unknown role of the cGAS-STING pathway in AD amyloid pathology and cognitive impairment, identifying the cGAS-STING pathway as a key molecular link between innate immunity and AD and reveal the complex interactions
between microglia, astrocytes, and neurons in the neuroinflammatory microenvironment.
Future research is necessary to further explore how neurodegenerative changes are carefully modulated by innate or adaptive immunity, and whether these harmful effects on neuronal function can be partially improved or even reversed
.
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The content is [iNature]
