Investigating the role of cGAS signaling and microglial senscence in tauopathy
Project Number3K99AG078493-02S1
Former Number5K99AG078493-02
Contact PI/Project LeaderAMIN, SADAF
Awardee OrganizationWEILL MEDICAL COLL OF CORNELL UNIV
Description
Abstract Text
PROJECT SUMMARY
Innate immune antiviral pathways are upregulated in Alzheimer’s disease (AD) and are thought to drive AD
pathogenesis. The specific mediators of maladaptive antiviral responses in AD are still not understood. Innate
immune system utilizes a series of nucleic acid sensors to detect viral genetic material to activate interferon
expression. The central DNA sensor in the cell is cyclic GMP-AMP synthase (cGAS). cGAS signaling has
emerged as an important player in many neurodegenerative diseases like Parkinson’s disease and amyotrophic
lateral sclerosis. The role of cGAS signaling in tau-mediated neurodegeneration remains unstudied. We discover
that cGAS signaling is hyperactivated in the brains of mice expressing mutant tau (P301S mice) and human AD
patients. Using behavioral assays, electrophysiological readings and single nuclei RNA sequencing, our
preliminary results indicate that cGAS activity modifies both the cellular responses to and the functional deficits
caused by tauopathy. We observed that partial or complete loss of Cgas rescued tauopathy-associated spatial
learning and memory deficits. cGAS is highly enriched in immune cells including microglia. We find that tau
induces a cGAS-dependent interferon signature by triggering mitochondrial DNA stress in microglia and show
that Cgas deletion alters microglial disease transformation, characterized by reduced expression of interferon
genes in disease microglia. It is not known how tau can alter mitochondrial and nuclear dynamics to activate
cGAS and how cGAS activation enhances neurotoxic effects of tau. This proposal will investigate the
mechanisms and consequences of cGAS and nucleic acid sensing pathways in tauopathy. I aim to dissect the
molecular mechanism of cGAS activation in response to tau by focusing on tau dependent cellular processes
that induce mitochondrial stress and microglial senescence (Aim 1) and investigate how cGAS mediates
maladaptive microglial responses and neuronal damage in tauopathy (Aim 2). Finally, since antiviral responses
could be species-specific, there is strong rationale to extend mouse studies of innate nucleic acid sensing to
human models. Human and mouse cGAS share only 60% amino acid similarity and have different activation
requirements. I will establish human pluripotent stem cell (hPSC)-based platforms to study broader nucleic acid
sensing pathways and perform unbiased CRISPR-screens to identify novel regulators of human nucleic acid
sensing in tau toxicity (Aim 3). The experiments outlined in this proposal will lead to a better understanding of
the role of nucleic acid sensors in tauopathy and AD which might prove translatable to humans.
Public Health Relevance Statement
PROJECT NARRATIVE
Alzheimer’s disease and tauopathies represent significant public health challenges. There is urgent need to
expand our knowledge of the underlying mechanisms of these conditions. In this proposal, we aim to dissect the
mechanisms underlying the pathogenic effects of aberrant anti-viral immune signaling by cyclic GMP-AMP
synthase (cGAS) to advance our understanding of how innate immune system contributes to neurodegeneration
and inform the development of more efficacious therapies.
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