title: Lack of insulin results in reduced seladin-1 expression in primary cultured neurons and in cerebral cortex of STZ-induced diabetic rats.
abstract: Several studies demonstrated that Diabetes mellitus (DM) enhances the risk for Alzheimer's disease (AD). Although hyperglycemia and perturbed function of insulin signaling have been proposed to contribute to AD pathogenesis, the molecular mechanisms behind this association is not clear yet. Seladin-1 is an enzyme catalyzing the last step in cholesterol biosynthesis converting desmosterol to cholesterol. The neuroprotective function of seladin-1 has gained interest in AD research recently. Seladin-1 has anti-apoptotic properties and regulates the expression of β-secretase (BACE-1). Here we measured seladin-1 mRNA and protein expressions in rat primary cultured neurons under diabetic conditions and also in the brains of rats with streptozotocine (STZ)-induced diabetes. We show that constant lack of insulin for 5days decreased seladin-1 levels in cultured rat primary neurons. Similarly, a decrease in seladin-1 was found in the brains of rats with STZ-induced diabetes. However, if the lack of insulin and/or high glucose treatment was intermittent, neuronal seladin-1 levels were not affected in vitro. On the other hand, treatment of neurons with metformin resulted in a significant increase in seladin-1. Constant lack of insulin for 5days, as well as high glucose treatment, increased the neuronal expression of BACE-1 in vitro, but not in the in vivo model. Our study defines insulin as a regulator of seladin-1 expression for the first time. The relevance of these findings for the association of DM with AD is discussed.
authors.affiliation: Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, 06100, Sihhiye, Ankara, Turkey. Electronic address: inci.kazkayasi@hacettepe.edu.tr.
authors.forename: Inci
authors.initials: I
authors.lastname: Kazkayasi
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institute, 14157, Huddinge, Sweden.
authors.forename: Muhammad-Al-Mustafa
authors.initials: MA
authors.lastname: Ismail
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institute, 14157, Huddinge, Sweden.
authors.forename: Cristina
authors.initials: C
authors.lastname: Parrado-Fernandez
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.affiliation: Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, 06100, Sihhiye, Ankara, Turkey.
authors.forename: Can
authors.initials: C
authors.lastname: Pekiner
authors.affiliation: Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, 06100, Sihhiye, Ankara, Turkey.
authors.forename: Serdar
authors.initials: S
authors.lastname: Uma
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institute, 14157, Huddinge, Sweden.
authors.forename: Angel
authors.initials: A
authors.lastname: Cedazo-Minguez
authors.affiliation: Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, 06100, Sihhiye, Ankara, Turkey.
authors.forename: Nihan
authors.initials: N
authors.lastname: Burul-Bozkurt
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D003897:Desmosterol / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000172:deficiency*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism*; D061251:Primary Cell Culture; D051381:Rats; D013311:Streptozocin
chemical_list: D007328:Insulin; D009419:Nerve Tissue Proteins; D003897:Desmosterol; D013311:Streptozocin; C000600134:DHCR24 protein, rat; D044925:Oxidoreductases Acting on CH-CH Group Donors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat
keywords: Alzheimer’s disease; BACE-1; Diabetes mellitus; Insulin; Seladin-1