Lovastatin ameliorates alpha-synuclein accumulation and oxidation in transgenic mouse models of alpha-synucleinopathies.
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.
Koob
Andrew O
AO
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, USA.
Ubhi
Kiren
K
Paulsson
Johan F
JF
Kelly
Jeffery
J
Rockenstein
Edward
E
Mante
Michael
M
Adame
Anthony
A
Masliah
Eliezer
E
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D003712:Dendrites / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020961:Lewy Body Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008148:Lovastatin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D018800:Thy-1 Antigens / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D010982:Platelet-Derived Growth Factor; D018800:Thy-1 Antigens; D051844:alpha-Synuclein; D002784:Cholesterol; D008148:Lovastatin