Core C: Mouse Intervention and Neuropathy Core

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The Mouse Intervention and Neuropathology Core (Core C) will provide investigators of this Program Project Grant (PPG) with mouse models necessary to achieve their specific aims, and will perform mouse lifespan assays, drug treatments and characterize mouse phenotypes. The overarching goal of this PPG is to understand the role of LINE-1 (L1) retrotransposons in age-related pathologies. In the current funding cycle, we discovered that L1s trigger systemic inflammation by inducing an interferon response via the cGAS-STING pathway. Core C was instrumental in showing that treatment of mice with nucleoside reverse transcriptase inhibitor (NRTI) drugs alleviates multiple pathologies and reduces inflammation. In the next funding cycle, we will focus on the role of L1-mediated inflammation in Alzheimer’s disease and determine whether inhibition of L1s rescues AD pathology in mouse models. Core C Specific Aims will be to: (1) Prepare and maintain the Institutional Animal Care and Use Committee protocols for all projects within this PPG; (2) Generate a ‘bat-STING’ mouse model to test whether dampened STING signaling alleviates AD pathology. This will be done in collaboration with Project 3 by making a mouse line, using CRISPR-Cas9, in which the conserved mouse Ser358 in STING is mutated to Ala. Ala358 is found in all bat species and results in dampened signaling and reduced inflammation. (3) Breed and maintain mice for project investigators; distribute mouse specimens to the projects. We will breed Annihilator, SIRT6-OE, STING KO, bat-STING and L1 reporter mice to MAPT and 5xFAD mouse models of AD for Projects 1 and 3. Multiple tissues including different regions of the brain will be harvested from mice of different ages for genomic, transcriptomic, and histological analyses. (4) Establish and maintain mouse aging colonies for Projects 1 and 3. Mouse models with genetically silenced L1 elements will be bred to MAPT and 5xFAD mouse models. Determine mouse healthspan and lifespan. (5) Treat MAPT and 5xFAD mouse models with NRTIs (FTC) for Projects 1 and 3 and determine the effect of the treatment on mouse life/health span and cognition. (6) Examine mouse physical and cognitive performance for Projects 1 and 3. (7) Generate transgenic mice with mutations in genes involved in transposon surveillance identified by Project 2. Multiple tissues including different regions of the brain will be harvested and provided to Projects 1, 2 and Core B for analysis of transposon expression and inflammation. (8) Maintain a database of all mice to ensure efficient distribution of materials and data to project investigators. Maintaining the centralized rodent colonies will standardize husbandry conditions, quality control and biological samples for use across the PPG projects, improve reproducibility of results, and allow the analysis of the same individual animals by several assays and projects, as well as minimize animal use.