β-Amyloid hyperproduction has been observed in response to alterations in neuronal intracellular cholesterol storage, efflux, and synthesis, induced in rats by a high-fat diet. It has been suggested that cholesterol homeostasis is altered in Alzheimer's disease resulting in higher β- and γ-secretase activity. In the current study the neuronal activation status of sterol regulatory element binding protein 2 (SREBP2) as well as its involvement in β-secretase BACE1 activity was investigated in high-fat fed rats (26\% fat and 4\% cholesterol for 20 weeks), and in SK-N-BE neuroblastoma cells exposed to 20 μM cholesterol. This work demonstrates that in the brain a hyperlipidic diet is able to induce a hyper-expression of BACE1 and determine an unbalance in cerebral cholesterol homeostasis so that SREBP2 is activated. In addition, we show for the first time the involvement of SREBP2 on expression of BACE1 in SK-N-BE cells exposed to high cholesterol. Although the enhanced risk of Alzheimer's disease in metabolic syndrome is related to several factors, our results suggest that SREBP2, which can be modulated by the impairment of cerebral cholesterol homeostasis, has a direct role on BACE1 expression and may be involved in Alzheimer's disease progression.

Dysregulation of SREBP2 induces BACE1 expression.

MASTROCOLA, Raffaella;GUGLIELMOTTO, Michela;MEDANA, Claudio;CATALANO, Maria Graziella;CUTRUPI, SANTINA;TAMAGNO, Elena;BOCCUZZI, Giuseppe;ARAGNO, Manuela
2011

Abstract

β-Amyloid hyperproduction has been observed in response to alterations in neuronal intracellular cholesterol storage, efflux, and synthesis, induced in rats by a high-fat diet. It has been suggested that cholesterol homeostasis is altered in Alzheimer's disease resulting in higher β- and γ-secretase activity. In the current study the neuronal activation status of sterol regulatory element binding protein 2 (SREBP2) as well as its involvement in β-secretase BACE1 activity was investigated in high-fat fed rats (26\% fat and 4\% cholesterol for 20 weeks), and in SK-N-BE neuroblastoma cells exposed to 20 μM cholesterol. This work demonstrates that in the brain a hyperlipidic diet is able to induce a hyper-expression of BACE1 and determine an unbalance in cerebral cholesterol homeostasis so that SREBP2 is activated. In addition, we show for the first time the involvement of SREBP2 on expression of BACE1 in SK-N-BE cells exposed to high cholesterol. Although the enhanced risk of Alzheimer's disease in metabolic syndrome is related to several factors, our results suggest that SREBP2, which can be modulated by the impairment of cerebral cholesterol homeostasis, has a direct role on BACE1 expression and may be involved in Alzheimer's disease progression.
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http://dx.doi.org/10.1016/j.nbd.2011.06.010
Amyloid Precursor Protein Secretases; biosynthesis, Animals, Aspartic Acid Endopeptidases; biosynthesis, Blotting; Western, Body Weight; drug effects/genetics, Brain; drug effects/enzymology, Cell Line; Tumor, Cell Nucleus; metabolism, Cholesterol; Dietary; pharmacology, Chromatin Immunoprecipitation, Chromatography; Gas, Chromatography; High Pressure Liquid, Cytosol; metabolism, Diet, Gene Expression Regulation; genetics/physiology, Glucose Tolerance Test, Hydroxycholesterols; metabolism, Insulin; blood, Lipids; blood, Male, Neurons; enzymology/physiology, RNA Interference, Rats, Reverse Transcriptase Polymerase Chain Reaction, Sterol Regulatory Element Binding Proteins; genetics/physiology, Tissue Extracts; metabolism
R. Mastrocola;M. Guglielmotto;C. Medana;M. G. Catalano;S. Cutrupi;R. Borghi;E. Tamagno;G. Boccuzzi;M. Aragno
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/154655
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