Neurochemical Research

, Volume 38, Issue 3, pp 589–600

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

  • Ai Hosaka
  • Wataru Araki
  • Akiko Oda
  • Yasushi Tomidokoro
  • Akira Tamaoka
Original Paper

DOI: 10.1007/s11064-012-0956-1

Cite this article as:
Hosaka, A., Araki, W., Oda, A. et al. Neurochem Res (2013) 38: 589. doi:10.1007/s11064-012-0956-1

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.

Keywords

Aβ APP Cholesterol Neuron Phosphorylation Statin 

Supplementary material

11064_2012_956_MOESM1_ESM.tif (380 kb)
Supplementary material 1 (TIFF 380 kb)

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Ai Hosaka
    • 1
    • 2
  • Wataru Araki
    • 1
  • Akiko Oda
    • 2
  • Yasushi Tomidokoro
    • 2
  • Akira Tamaoka
    • 2
  1. 1.Department of Demyelinating Disease and AgingNational Institute of Neuroscience, NCNPTokyoJapan
  2. 2.Department of Neurology, Faculty of MedicineUniversity of TsukubaTsukubaJapan

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