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

被引：90

作者：

Koob, Andrew O. ^{[1
,2
]}

Ubhi, Kiren ^{[1
]}

Paulsson, Johan F. ^{[3
,4
]}

Kelly, Jeffery ^{[3
,4
]}

Rockenstein, Edward ^{[1
]}

Mante, Michael ^{[1
]}

Adame, Anthony ^{[1
]}

Masliah, Eliezer ^{[1
,5
]}

机构：

[1] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[2] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[3] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA

[4] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[5] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA

来源：

EXPERIMENTAL NEUROLOGY | 2010年 / 221卷 / 02期

关键词：

Cholesterol inhibitors; Parkinson's disease; Dementia with Lewy bodies; Neurodegeneration; Statins; COENZYME-A REDUCTASE; ALZHEIMERS-DISEASE; IN-VITRO; PRESYNAPTIC PROTEIN; PARKINSONS-DISEASE; LEWY BODIES; CHOLESTEROL; AGGREGATION; BARRIER; BRAIN;

D O I：

10.1016/j.expneurol.2009.11.015

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Alpha-synuclein (alpha-syn) aggregation is a neuropathological hallmark of many diseases including Dementia with Lewy Bodies (DLB) and Parkinson's Disease (PD), collectively termed the alpha-synucleinopathies. The mechanisms underlying alpha-syn aggregation remain elusive though emerging science has hypothesized that the interaction between cholesterol and alpha-syn may play a role. Cholesterol has been linked to alpha-synucleinopathies by recent work suggesting cholesterol metabolites appear to accelerate alpha-syn fibrillization. Consistent with these findings, cholesterol-lowering agents have been demonstrated to reduce alpha-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 alpha-syn aggregation in two different transgenic (Tg) mouse models that neuronally overexpress human alpha-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 alpha-syn aggregates and alpha-syn immunoreactive neuropil in the temporal cortex of lovastatin-treated Tg mice in comparison to saline-treated alpha-syn Tg controls. Consistently, immunoblot analysis of mouse brain homogenates showed a reduction in levels of total and oxidized alpha-syn in lovastatin-treated alpha-syn Tg mice in comparison to saline-treated alpha-syn Tg controls. The reduced alpha-syn accumulation in lovastatin-treated mice was associated with abrogation of neuronal pathology. The results from this study demonstrate that lovastatin administration can reduce alpha-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. (C) 2009 Elsevier Inc. All rights reserved.

引用

页码：267 / 274

页数：8

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