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標題: S-Adenosylhomocysteine increases beta-amyloid formation in BV-2 microglial cells by increased expressions of beta-amyloid precursor protein and presenilin 1 and by hypomethylation of these gene promoters
作者: Lin, H.C.
Hsieh, H.M.
Chen, Y.H.
Hu, M.L.
關鍵字: S-Adenosylhomocysteine;beta-Amyloid;Presenilin 1;Hypomethylation;alzheimers-disease;methylation status;dna methylation;homocysteine;adenosylmethionine;forebrain;secretase;cleavage;neurons;folate
Project: Neurotoxicology
期刊/報告no:: Neurotoxicology, Volume 30, Issue 4, Page(s) 622-627.
S-Adenosylhomocysteine (SAH) has been implicated as a risk factor for neurodegenerative diseases such as Alzheimer's disease. As SAH is a potent inhibitor of all cellular methyltransferases, we herein examined the hypothesis that SAH may increase the formation of amyloid beta-peptide (A beta) in BV-2 mouse microglial cells through hypomethylation of presenilin 1 protein (PSI) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), both of which cleave A beta precursor protein (APP) to form A beta. The results showed that SAH increased A beta protein formation in a concentration-dependent manner (10500 nM), and this effect of SAH was accompanied by significantly increased expression of APP and PS1 proteins, although SAH only significantly increased the expression of BACE1 at the highest concentration used (500 nM). SAH (500 nM) markedly induced hypomethylation of APP and PS1 gene promoters. Incubation of cells with 5'-azc (20 mu M), also an inhibitor of DNA methyltransferases enhanced A beta protein expression and APP and PSI gene promoters hypomethylation. By contrast, pre-incubation of cells with betaine (1.0 mM), 30 min followed by incubation with SAH (500 nM) or 5'-azc (20 mu M) for 24 h markedly prevented the expression of A beta protein (by 50%, P < 0.05) and the gene promoter hypomethylation of APP and PS1. Taken together, this study demonstrates that SAH increases the production of A beta in BV-2 cells possibly by increased expression of APP and induction of hypomethylation of APP and PSI gene promoters. (C) 2009 Elsevier Inc. All rights reserved.
ISSN: 0161-813X
DOI: 10.1016/j.neuro.2009.03.011
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