Role of cGAS-Sting Signaling in Alzheimer's Disease

Abstract

There is mounting evidence that the development of Alzheimer's disease (AD) interacts extensively with immunological processes in the brain and extends beyond the neuronal compartment. Accumulation of misfolded proteins can activate an innate immune response that releases inflammatory mediators and increases the severity and course of the disease. It is widely known that type-I interferon-driven neuroinflammation in the central nervous system (CNS) accelerates the development of numerous acute and chronic CNS diseases. It is becoming better understood how the cyclic GMP-AMP synthase (cGAS) and its adaptor protein Stimulator of Interferon Genes (STING) triggers type-I IFN-mediated neuroinflammation. We discuss the principal elements of the cGAS-STING signaling pathway and the mechanisms underlying the association between cGAS-STING activity and various AD pathologies. The current understanding of beneficial and harmful cGAS-STING activity in AD and the current treatment pathways being explored will be discussed in this review. The cGAS-STING regulation offers a novel therapeutic opportunity to modulate inflammation in the CNS because it is an upstream regulator of type-I IFNs.

Keywords: Alzheimer’s disease; STING; cGAS; neuroinflammation; type-I IFN.

Figure 1

A schematic representation of double-stranded DNA (dsDNA)-induced activation of cytosolic cyclic GMP–AMP synthase (cGAS). Viral infection, mitochondrial damage, micronuclei or cellular stress leads to increased accumulation of cytoplasmic dsDNA, which binds to cGAS. On binding dsDNA, cGAS dimers assemble on dsDNA leading to enzymatic activation of cGAS and synthesis of 2′3′ cyclic GMP–AMP (cGAMP). The cGAMP binds to stimulator of interferon genes (STING) dimers present at the endoplasmic reticulum (ER) membrane, leading to profound conformational changes that trigger STING activation. STING recruits TANK-binding kinase 1 (TBK1), promoting TBK1 autophosphorylation and phosphorylation of interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 translocates to the nucleus to induce gene expression of type I interferons and several other inflammatory mediators, pro-apoptotic genes and chemokines.

Figure 2

Potential signaling pathways involved in AD pathogenesis. Extracellular accumulation of β-amyloid plaques leads to either mitochondrial damage or impaired mitophagy leading to release of mitochondrial DNA into the cytosol. Impaired autophagy and cellular stress lead to accumulation of cytoplasmic dsDNA leading to the activation of the cGAS–STING pathway. Neurofibrillary tangles (NFT) can induce reverse transcription of transposable elements in the nucleus, leading to the accumulation of dsDNA. Alternatively, PGBP1 acts as an intracellular receptor for tau and activates the cGAS–STING pathway, which subsequently activates either the IRF3 or NF-κB pathway, leading to DNA-driven inflammatory response.