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Statins Reduce Amyloid β-Peptide Production by Modulating Amyloid Precursor Protein Maturation and Phosphorylation Through a Cholesterol-Independent Mechanism in Cultured Neurons

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Abstract

Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have been reported to attenuate amyloid-β peptide (Aβ) production in various cellular models. However, the mechanisms by which statins affect neuronal Aβ production have not yet been clarified. Here, we investigated this issue in rat primary cortical neurons using two statins, pitavastatin (PV) and atorvastatin (AV). Treatment of neurons with 0.2–2.5 μM PV or AV for 4 days induced a concentration- and time-dependent reduction in the secretion of both Aβ40 and Aβ42. Moreover, Western blot analyses of cell lysates showed that treatment with PV or AV significantly reduced expression levels of the mature form of amyloid precursor protein (APP) and Thr668-phosphorylated APP (P-APP), but not immature form of APP; the decreases in P-APP levels were more notable than those of mature APP levels. The statin treatment did not alter expression of BACE1 (β-site APP-cleaving enzyme 1) or γ-secretase complex proteins (presenilin 1, nicastrin, APH-1, and PEN-2). In neurons overexpressing APP via recombinant adenoviruses, PV or AV similarly reduced Aβ secretion and the levels of mature APP and P-APP. Statins also markedly reduced cellular cholesterol content in neurons in a concentration-dependent manner. Co-treatment with mevalonate reversed the statin-induced decreases in Aβ secretion and mature APP and P-APP levels, whereas co-treatment with cholesterol did not, despite recovery of cellular cholesterol levels. Finally, cell-surface biotinylation experiments revealed that both statins significantly reduced the levels of cell-surface P-APP without changing those of cell surface mature APP. These results suggest that statins reduce Aβ production by selectively modulating APP maturation and phosphorylation through a mechanism independent of cholesterol reduction in cultured neurons.

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Acknowledgments

We thank Drs. Fuyuki Kametani, Steven G. Younkin, Goapal Thinakaran for anti-APP C-terminal, anti-APP N-terminal, and anti-PEN-2 antibodies, respectively. This work was supported by Grants from the Ministry of Health, Labor, and Welfare, Japan, and a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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All the authors declared no competing interests.

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Authors and Affiliations

  1. Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan

    Ai Hosaka & Wataru Araki

  2. Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan

    Ai Hosaka, Akiko Oda, Yasushi Tomidokoro & Akira Tamaoka

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  1. Ai Hosaka
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  2. Wataru Araki
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Correspondence to Wataru Araki.

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Hosaka, A., Araki, W., Oda, A. et al. Statins Reduce Amyloid β-Peptide Production by Modulating Amyloid Precursor Protein Maturation and Phosphorylation Through a Cholesterol-Independent Mechanism in Cultured Neurons. Neurochem Res 38, 589–600 (2013). https://doi.org/10.1007/s11064-012-0956-1

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  • DOI: https://doi.org/10.1007/s11064-012-0956-1

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