Microglial RGS10 as a therapeutic target for Lewy body diseases

总结 与衰老相关的炎症和代谢紊乱，包括阿尔茨海默病（AD）、路易体痴呆 (LBD)和路易体痴呆（DLB），对人类健康构成严重威胁，因为它们是风险 痴呆的因素。小胶质细胞在中枢神经系统的免疫监视中起关键作用， 聚集，并维持能量平衡和新陈代谢。然而，小胶质细胞经历表型 神经退行性疾病期间的变化，并导致神经退行性疾病。所以我们 可能能够利用小胶质细胞的活性并恢复代谢稳态，作为一种有效的治疗方法， 治疗与年龄相关的神经退行性疾病 这项建议的目的是 形成一种小胶质细胞特异性的 由靶向小胶质细胞的抗体组成的用于淀粉样蛋白纤维诱导的神经变性的纳米颗粒 （Tmem 119）和编码G蛋白信号传导调节子10的质粒（pRGS 10）。 RGS 10是一种自我平衡的 小胶质细胞中的蛋白质及其水平随着慢性炎症和衰老而显著降低。我们的初步 研究表明，RGS 10增强了对异常聚集蛋白的吞噬作用，包括纤维状β- 淀粉样蛋白（fAβ）和α-突触核蛋白（α-syn）。我们假设，通过小胶质细胞特异性表达RGS 10， 携带pRGS 10的纳米颗粒可以恢复小胶质细胞的稳态，增强淀粉样蛋白原纤维的清除， 提供针对淀粉样蛋白原纤维诱导的神经元死亡的神经保护。我们将利用两项创新 方法：一种新型的阳离子两亲性共聚物，聚（丙交酯-共-乙交酯）-接枝-聚乙烯亚胺（PgP）： 和路易体病的预形成原纤维（PFF）α-syn小鼠模型（PFF小鼠模型），以确定 小胶质细胞RGS 10具有神经保护作用。在目的1中，我们将抗Tmem 119 mAb缀合到PgP表面， （Tmem-PgP），配制Tmem-PgP/pRGS 10纳米颗粒并评估靶向特异性和神经保护 在原代神经元/小胶质细胞共培养系统中。在目标2中，我们将证明 Tmem-PgP/pRGS 10在PFF小鼠模型中的表达。这项研究的完成将阐明RGS 10在以下方面的作用： 维持小胶质细胞稳态条件，以及我们如何利用RGS 10作为治疗靶点， 淀粉样纤维相关的神经退行性疾病。

SUMMARY Aging-related inflammation and metabolic disorders, including Alzheimer's disease (AD), Lewy body dementia (LBD), and Dementia with Lewy bodies (DLB), constitute serious threats to human health as they are risk factors for dementia. Microglia play a critical role in immune surveillance in the CNS, clearing abnormal protein aggregates, and maintaining energy balance and metabolism. However, microglia undergo phenotypic changes during neurodegenerative disorders and contribute to neurodegenerative diseases. Therefore, we may be able to harness the activity of microglia and restore metabolic homeostasis as an effective therapeutic for age-related neurodegenerative disorders. The objective of this proposal is to develop a microglia-specific nanotherapeutic for amyloid fibrils-induced neurodegeneration composed of an antibody targeting to microglia (Tmem119) and plasmid encoding regulator of G-protein signaling 10 (pRGS10). RGS10 is a homeostatic protein in microglia and its level is significantly decreased with chronic inflammation and aging. Our preliminary study demonstrated that RGS10 enhances phagocytosis of abnormally aggregated proteins including fibrillar β- amyloid (fAβ) and α-synuclein (α-syn). We hypothesize that enriching RGS10 levels through microglia-specific nanoparticles carrying pRGS10 may restore microglial homeostasis, enhance amyloid fibril clearance, and provide neuroprotection against amyloid-fibril-induced neuronal death. We will utilize two innovative approaches: a novel cationic amphiphilic co-polymer, poly (lactide-co-glycolide)-graft-polyethylenimine (PgP): and a preformed fibril (PFF) α-syn mouse model of Lewy body diseases (PFF mouse model) to determine if microglial RGS10 is neuroprotective. In Aim 1, we will conjugate anti-Tmem119 mAb to the surface of PgP (Tmem-PgP), formulate Tmem-PgP/pRGS10 nanoparticles and evaluate target-specificity and neuroprotection in a primary neuron/microglia co-culture system. In Aim 2, we will demonstrate the therapeutic efficacy of Tmem-PgP/pRGS10 in the PFF mouse model. The completion of this study will elucidate the role of RGS10 in maintaining microglia homeostatic conditions and how we may utilize RGS10 as a therapeutic target for amyloid fibril-associated neurodegenerative diseases.