Table 2 Research evidence on the correlation between the cGAS-STING pathway and AD

APP/PS1 mice;

Aβ induced HMC3 human microglial cells

-

Upregulated cGAS, STING

Increased cytosolic mtDNA level

NAD⁺

Decreased cytoplasmic mtDNA, cGAS, STING levels

Reduced neuroinflammation; improved cognition impairment and synaptic plasticity; prevented cellular senescence; promoted the protective microglial phenotype

[167]

5xFAD mice

Hippocampal region of AD patients

Upregulated cGAS, STING

Increased cytosolic mtDNA level

Cgas − / − ;

RU.521;

H-151

Suppressed the activation of the cGAS-STING pathway

Alleviated cognitive impairment, Aβ pathology, neuroinflammation; inhibited neurotoxic A1 astrocytic phenotype in microglia

[145]

APP/PS1 mice

-

Upregulated cGAS, STING

Increased cytosolic dsDNA level

Tetrahydroxy stilbene glycoside

Decreased cGAS, STING; alleviated the accumulation of cytosolic DNA

Ameliorated neuroinflammation; improved cognition impairment; inhibited the polarization of microglia toward M1-type

[169]

5 × FAD mice

-

Upregulated cGAS, STING

-

Cgas deletion;

H-151

-

Suppressed the formation of neurotoxic A1 astrocytes; decreased oligomeric Aβ-induced neuronal toxicity

[170]

5xFAD mice

AD patients

Upregulated cGAS, STING

-

Microglia-specific cGAS knockout

-

Alleviated Aβ-induced cognitive impairment;

limited plaque formation; reduced the levels of dystrophic neurites

[117]

APP/PS1 mice; sporadic AD patients derived-human skin fibroblast cell line

-

Upregulated cGAS, STING

Increased mtDNA level

NR

Elevated the cGAS-STING was normalized; reduced cytoplasmic DNA levels

Increased mitophagy; reduced neuroinflammation and cellular senescence; improved cognition and behavior; promotes anti-inflammatory microglial polarization

[171]

-

Temporal lobe of AD patients

Impaired cGAS-STING-interferon signaling

Increased dsDNA damage

-

-

-

[172]

PLD3 deficient SH-SY5Y cells

-

Upregulated cGAS, STING

Increased mtDNA level in lysosomes and cytoplasm

APP knockout;

H151

Lowered STING activation;

Normalized APP-CTF levels and cholesterol biosynthesis

[173]

-

AD patients, dapsone, and anti-AD drug users in Hansen subjects

-

-

Dapsone (cGAS-STING pathway inhibitor)

-

Prevented AD exacerbation

[174]

APP/PS1 mice

AD patients

Downregulated cGAS, STING

Increased cytosolic mtDNA level

Melatonin

Promoting the cGAS-STING signaling; Ameliorated cytosolic mtDNA accumulation

Ameliorated APP/PS1-induced changes in cardiac geometry and function, apoptosis, mitochondrial integrity, and mitophagy

[175]

AD patient derived-iPSCs

-

Upregulated cGAS, STING

Increased cytosolic RNA–DNA hybrids level

c-Jun inhibition

Rescue RNA–DNA hybrid formation and the cGAS-STING activation

Rescued neuronal death and the impaired neurogenesis phenotype in AD progenitors

[166]

Aβ induced microglia

-

Upregulated cGAS, STING

-

RU.521;

C-176;

IFITM3 Knockdown

Decreased cGAS, STING

Suppressed the M1-like polarization of microglia; reduced neuroinflammation

[176]

APP/PS1 mice; Aβ induced HT22, N2a and SK‐N‐BE cell lines

-

Upregulated STING

Increased mtDNA leakage

Knocking out STING

Decreased STING

Inhibited Aβ1–42 and mtDNA induced neuron degeneration and cognitive impairment

[177]

STZ-treated HT22 murine hippocampal neurons; ICV-STZ rats

-

Upregulated STING

-

Silibinin

Decreased STING

Promoted survival of STZ-treated HT22 cells; ameliorates the cognitive impairment and anxiety/depression-like behavior of ICV-STZ rats; reduces STING-mediated neuroinflammation

[178]

P301S transgenic mice; tau induced microglia

AD patients

Upregulated cGAS, STING

Increased cytosolic mtDNA level

Cgas loss;

TDI-6570

-

Restored synaptic integrity, plasticity and memory

[103]

APP/PS1 mice

-

Downregulated STING

-

cGAMP

Upregulated the expression of STING

Ameliorates cognitive deficits; improved pathological changes; decreases Aβ plaque load and neuron apoptosis

[179]

App^NL−G−F/hTau double-knock-in mice;

APOE ε4 human iPSC-derived microglia;

Primary microglia treated with Aβ and tau

-

Upregulated cGAS, STING

Increased cytosolic mtDNA level

H-151;

SN-011;

STING knockout

Decreased STING

Reduced a wide range of AD pathogenic features; reduced gliosis and cerebral inflammation; prevented memory loss

[180]

APOE4-R47H female tauopathy mice

-

Upregulated cGAS, STING

Increased cytosolic mtDNA level

-

-

-

[181]