ENGINEERED HUMAN MICROGLIA AS A CELL-BASED THERAPY FOR A-BETA PLAQUE REMOVAL

项目摘要 AD是年龄相关性痴呆的最常见原因，其特征在于脑内神经元的进行性损伤。 认知功能在病理学上，AD患者表现出Aβ斑块和神经元缠结， 神经元和突触丧失。不幸的是，对于这种毁灭性的疾病仍然没有有效的治疗方法。 失败可能源于症状前10-20年的淀粉样蛋白积累和有限的血脑屏障 (BBB)许多候选疗法的替代品。早期诊断加上有效和持续的 因此，脑内治疗源可以提供改善AD病理学的强有力的方法。在此我们 探索一种将治疗有效载荷输送到大脑中以治疗Aβ斑块负荷的变革性方法。 我们将测试工程化的人类小胶质细胞是否可以被设计成安全有效地将治疗药物输送到小鼠体内。 AD模型第一个具体目标是通过确定变更来证明该方法的可行性 在Aβ负载的工程化小胶质细胞移植中。第二个目标将确定是否减少Aβ斑块负荷 导致长时程增强缺陷的挽救。总的来说，这R21准备测试的可行性， 安全有效地提供治疗以对抗AD中Aβ斑块积聚的变革性方法。 这种方法的成功演示可能对治疗药物的提供产生深远的影响 进入大脑

PROJECT SUMMARY AD is the most common cause of age-related dementia, and is characterized by a progressive impairment in cognitive function. Pathologically, AD patients exhibit Aβ plaques and neurofibrillary tangles with extensive neuronal and synaptic loss. Unfortunately, there is still no effective treatment for this devastating disease. Failures likely arise from amyloid accumulation 10-20 years prior to symptoms and the limited blood brain barrier (BBB) penetrance of many candidate therapies. Earlier diagnoses coupled with an effective and continuous source of in-brain therapy may therefore provide a powerful approach to ameliorate AD pathology. Herein we explore a transformative approach toward delivering therapeutic payloads into the brain to treat Aβ plaque load. We will test if engineered human microglia can be designed to safely and effectively deliver therapies into mouse models of AD. The first specific aim is to demonstrate the feasibility of the approach by determining the change in Aβ load with engineered microglia transplantation. The second aim will determine if reduced Aβ plaque load results in rescue of long-term potentiation defects. Overall, this R21 is poised to test the feasibility of novel and transformative approaches for safe and effective delivery of therapies to combat Aβ plaque buildup on AD. Successful demonstration of this approach could have far-reaching implications for the delivery of therapeutics into the brain.