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.