Lovastatin ameliorates α-synuclein accumulation and oxidation in transgenic mouse models of α-synucleinopathies

Abstract

Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of many diseases including Dementia with Lewy Bodies (DLB) and Parkinson's Disease (PD), collectively termed the α-synucleinopathies. The mechanisms underlying α-syn aggregation remain elusive though emerging science has hypothesized that the interaction between cholesterol and α-syn may play a role. Cholesterol has been linked to α-synucleinopathies by recent work suggesting cholesterol metabolites appear to accelerate α-syn fibrillization. Consistent with these findings, cholesterol-lowering agents have been demonstrated to reduce α-syn accumulation and the associated neuronal pathology in vitro. In this context, this study sought to investigate the in vivo effects of the cholesterol synthesis inhibitor lovastatin on α-syn aggregation in two different transgenic (Tg) mouse models that neuronally overexpress human α-syn. Lovastatin-treated mice displayed significantly reduced plasma cholesterol levels and levels of oxidized cholesterol metabolites in the brain in comparison to saline-treated controls. Immunohistochemical analysis demonstrated a significant reduction of neuronal α-syn aggregates and α-syn immunoreactive neuropil in the temporal cortex of lovastatin-treated Tg mice in comparison to saline-treated α-syn Tg controls. Consistently, immunoblot analysis of mouse brain homogenates showed a reduction in levels of total and oxidized α-syn in lovastatin-treated α-syn Tg mice in comparison to saline-treated α-syn Tg controls. The reduced α-syn accumulation in lovastatin-treated mice was associated with abrogation of neuronal pathology. The results from this study demonstrate that lovastatin administration can reduce α-syn aggregation and associated neuropathology and support the possibility that treatment with cholesterol-lowering agents may be beneficial for patients with PD and/or DLB.