Microglial RGS10 as a therapeutic target for Lewy body diseases

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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.