PubMed:26931464 JSONTXT

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Of these three drugs, lovastatin had the highest lipophilicity, which facilitated crossing the blood-brain barrier. In LRRK2-G2019S knock-in mice and stably transfected human dopaminergic cells, lovastatin significantly rescued neurite degeneration in a dose-dependent manner, within a range of 0.05-0.1 μm The beneficial effect of lovastatin was exerted by activating anti-apoptotic Akt/Nrf signaling and decreasing caspase 3 levels. We also observed that lovastatin inhibited GSK3β activity, a kinase downstream of Akt, by up-regulating GSK3β (Ser9) phosphorylation. This inhibition subsequently decreased tau phosphorylation, which was linked to neuronal cytoskeleton instability. Conversely, pre-treatment with the Akt inhibitor, A6730, blocked the lovastatin-induced neuroprotective effect. The rescuing effects of lovastatin in dendritic arborization of LRRK2-G2019S neurons were abolished by co-expressing either a mutant allele of Akt (Akt1(04226)) or a constitutively active form of GSK3β (sgg(S9A)). Our findings demonstrated that lovastatin restored LRRK2-G2019S neurite degeneration by augmenting Akt/NRF2 pathway and inhibiting downstream GSK3β activity, which decreased phospho-tau levels. We suggested that lovastatin is a potential disease-modifying agent for LRRK2-G2019S 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