Administrative Supplement: Strategies for Targeting Astrocyte Reactivity in Alzheimer's Disease and Related Dementias

CORE A Supplement: Abstract-Summary This supplement will operate under the umbrella of Core A of the parent P01 to support the generation of new transgenic mouse lines in which genes-of-interest can either be expressed or knocked down (using doxycycline inducible system) selectively in brain astrocytes. Two lines will be created for each research project (an “Astro- on” and an “Astro-off” line) to target signaling constituents relevant to the reactive astrocyte phenotype and linked to Alzheimer’s disease (AD) or AD-related dementias (ADRDs): MMP9 (Project 1), IRβ (Project 2), SLC1A2 (Project 3), and SUR2B (Project 4). New mouse models will significantly provide greater consistency in terms of (1) the uniformity of astrocytes targeted and (2) the extent of overexpression/knock-down. This advance is expected to reduce mouse-to-mouse variability and increase statistical power. New transgenic models will also streamline study design by eliminating the need for injecting multiple AAV reagents (e.g. one AAV for astrocyte targeting, another AAV for measuring Ca2+) in a single mouse at different time points. This advance will greatly simplify data interpretation, while simultaneously reducing the number of invasive procedures per mouse. Finally, new transgenic models will be readily available to the scientific community to verify our findings or generate new avenues of research, which will promote experimental rigor and further delineate the role of reactive astrocytes in ADRDs.