title: Simvastatin and atorvastatin facilitates amyloid β-protein degradation in extracellular spaces by increasing neprilysin secretion from astrocytes through activation of MAPK/Erk1/2 pathways.
abstract: One of the major neuropathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid β-protein (Aβ) in the brain. Aβ accumulation seems to arise from an imbalance between Aβ production and clearance. Neprilysin (NEP) and insulin-degrading enzyme (IDE) are the important Aβ-degrading enzymes in the brain, and deficits in their expression may promote Aβ deposition in patients with sporadic late-onset AD. Statins, which are used clinically for reducing cholesterol levels, can exert beneficial effects on AD. Therefore, we examined whether various statins are associated with Aβ degradation by inducing NEP and IDE expression, and then evaluating the relation between activation of intracellular signaling transduction, inhibition of cholesterol production, and morphological changes to astrocytes. Treating cultured rat astrocytes with simvastatin and atorvastatin significantly decreased the expression of NEP but not IDE in a concentration- and time-dependent manner. The decrease in NEP expression was a result of activation of extracellular signal-regulated kinase (ERK) but not the reduction of cholesterol synthesis pathway. This NEP reduction was achieved by the release to the extracellular space of cultured astrocytes. Furthermore, the cultured medium prepared from simvastatin- and atorvastatin-treated astrocytes significantly induced the degradation of exogenous Aβ. These results suggest that simvastatin and atorvastatin induce the increase of Aβ degradation of NEP on the extracellular of astrocytes by inducing ERK-mediated pathway activity and that these reagents regulate the differential mechanisms between the secretion of NEP, the induction of cholesterol reduction, and the morphological changes in the cultured astrocytes.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa, 920-1181, Japan.|Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Kasahara
authors.affiliation: Department of Physiology II, Kanazawa Medical University, Uchinada, Ishikawa, 920-0293, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tanida
authors.affiliation: Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ohora
authors.affiliation: Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ono
authors.affiliation: Laboratory of Molecular Medicinal Science, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, Nagoya City, Aichi, 467-8622, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Sobue
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D000069059:Atorvastatin / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D015260:Neprilysin / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000069059:Atorvastatin; D019821:Simvastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D015260:Neprilysin
keywords: Alzheimer's disease; cholesterol; protein metabolism