R01AG072758

Maladaptive Antiviral Pathways in Alzheimer's Disease - Abstract

Alzheimer's disease (AD) is the most common form of late-onset dementia. The extents of tau pathology are closely related to memory decline. How pathogenic tau causes cognitive deficits is not clear. While most studies on tau have been focused on direct effects of tau on neurons, compelling human genetic studies linked maladaptive innate immune responses, including microglial responses, to elevated risk of developing late-onset Alzheimer's disease. The striking enrichment of innate immune genes as risk alleles for Alzheimer's disease supports the critical disease-enhancing role of maladaptive microglia in tau-mediated cognitive deficits. Identifying how maladaptive microglial enhances tau toxicity could lead to new therapeutic strategies.

In our preliminary studies, we found that tauopathy mice exhibit hyperactive cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. As a major sensor of cytosolic DNA, cGAS-STING pathway mobilizes antiviral responses via activation of interferon regulatory factors (IRFs) and expression of cytokine and type I interferon genes. The hyperactive cGAS pathways contribute to tau toxicity since genetic reduction of cGAS protected against tau-mediated spatial learning and memory deficits in a tauopathy mouse model of Alzheimer's disease. In addition, the protective effects were associated with reduced interferon-enriched microglial subpopulations and reprogramming of disease-associated microglial states as identified using single nuclei RNA-seq.

We hypothesize that microglial cGAS-STING hyperactivation mediates the maladaptive disease-enhancing microglial response in tauopathy. To test this hypothesis, in Aim 1, we will first determine how cGAS activation in microglia enhances tau toxicity (1A). Using a combination of single nuclei RNA-seq, pathological and functional analyses, we will investigate if toxicity from cGAS hyperactivation in microglia or bone marrow-derived monocytes (1B, 1C). In Aim 2, we will dissect if the toxic effects of cGAS activation in tauopathy are mediated by STING-dependent or -independent mechanisms. We will determine if loss of STING phenocopies the effects of cGAS inactivation on tau toxicity and transcriptomic changes (2A). We will then determine STING-independent mechanisms of cGAS activation by assessing how cGAS inactivation affects tau toxicity on STING null background (2B). The significant protective effects of partial loss of cGAS support that partial inhibition with pharmacological inhibitors of cGAS could be beneficial for tauopathy.

We showed that a specific cGAS inhibitor, TDI6570, is brain permeable and effectively inhibits expression of type 1 interferon target genes in tauopathy mice. We will then optimize the dosing using formulated chow based on PK/PD, and evaluate the beneficial effects of the cGAS inhibitor before or after the onset of cognitive deficit in tauopathy mice in Aim 3. Completion of the proposed study will identify novel disease-enhancing properties of innate immune responses in AD and provide new therapeutic direction for pharmacological intervention.

Weill Medical College Of Cornell University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

New York, New York 100654805 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 394% from $830,711 to $4,105,042.