Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience

Abstract

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

The type‐I interferon response potentiates seeded tau aggregation and exacerbates tau pathology

“…Moreover, the treatment of microglia, the major site of pathogen detection in the brain, with Aβ fibrils, can promote the production of IFN‐I 14,16 . Tau fibrils may also promote microglial IFN‐I production, partially by promoting the release of mitochondrial deoxyribonucleic acid (DNA) into the cytosol 17 . However, the effects of IFN‐I on the development of tau pathology are unclear.…”

Neuroprotective Mechanisms of Salidroside in Alzheimer’s Disease: A Systematic Review and Meta-analysis of Preclinical Studies

“…8 A recent important study found that tau proteins are also involved in activating antiviral pathways and inhibit neuronal repair, ultimately leading to tau protein-induced cognitive impairment. 9 Furthermore, as research continues, evidence accumulates that supports the role of neuroinflammation, oxidative stress damage, and neuronal apoptosis in the pathogenesis of AD. 10 Although domestic and international research on AD continues unabated, many questions remain unresolved, and consequently, few new drugs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of AD since 2003.…”

“…Hyperphosphorylated tau proteins cannot bind to microtubule proteins, forming NFTs . A recent important study found that tau proteins are also involved in activating antiviral pathways and inhibit neuronal repair, ultimately leading to tau protein-induced cognitive impairment . Furthermore, as research continues, evidence accumulates that supports the role of neuroinflammation, oxidative stress damage, and neuronal apoptosis in the pathogenesis of AD …”

Single-Cell Secretion Analysis via Microfluidic Cell Membrane Immunosorbent Assay for Immune Profiling

“…Cellular secretions typically function as mediators of biosignal transduction and thus play an important role in a range of physiological and pathological processes. 1 For example, the levels of IFN-γ, IL-1b, IL-6, MCP-1, TNF-α, IL-2, and IL-5 are significantly elevated in the plasma of nasopharyngeal carcinoma (NPC) patients, subsequently undergoing a marked reduction following treatment. 2 Notably, as immune cells exhibit functional diversity, even the genetically homogeneous cells can demonstrate a range of different physiological functions, 3 due to the cell heterogeneous response to the varied clinical conditions.…”

“…Cellular secretions typically function as mediators of biosignal transduction and thus play an important role in a range of physiological and pathological processes . For example, the levels of IFN-γ, IL-1b, IL-6, MCP-1, TNF-α, IL-2, and IL-5 are significantly elevated in the plasma of nasopharyngeal carcinoma (NPC) patients, subsequently undergoing a marked reduction following treatment .…”