Strategies for targeting astrocyte reactivity in Alzheimer's disease and related dementias.

核心A补编：摘要--摘要 这一补充将在父P01的核心A的保护伞下运行，以支持新的 可表达或敲除目的基因(使用强力霉素)的转基因小鼠品系 诱导系统)选择性地在脑星形胶质细胞中表达。将为每个研究项目创建两条线(“Astro- 与反应性星形胶质细胞表型相关并连锁的信号成分 阿尔茨海默病(AD)或AD相关痴呆(ADRD)：MMP9(项目1)、IRβ(项目2)、SLC1A2 (项目3)和SUR2B(项目4)。新的鼠标模型将显著提供更大的一致性 (1)靶向星形胶质细胞的一致性和(2)过度表达/下调的程度。这一进步 预计将减少鼠标到鼠标的变异性，并增加统计能力。新的转基因模型将 此外，通过不需要注射多种AAV试剂(例如，一种AAV用于 星形胶质细胞靶向，另一种用于测量单个小鼠不同时间点钙离子浓度的AAV)。这一进步 将极大地简化数据解释，同时减少每个 老鼠。最后，新的转基因模型将随时提供给科学界，以验证我们的 发现或产生新的研究途径，这将促进实验的严谨性，并进一步描绘 反应性星形胶质细胞在ADRDS中的作用。

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.