title: Resveratrol Intervenes Cholesterol- and Isoprenoid-Mediated Amyloidogenic Processing of AβPP in Familial Alzheimer's Disease.
abstract: Deterioration of cholesterol metabolism has recently been a frontier subject of investigation in the field of Alzheimer's disease (AD). Though amyloid-β protein precursor (AβPP) primes the pathological cascade, changes in cholesterol levels and its intermediates, geranyl geranyl pyrophosphate and farnesyl pyrophosphate, is expected to have a different consequence on AβPP processing and amyloid-β (Aβ) generation. However, the use of statins (HMG-COA reductase inhibitor) has been widely implicated in slowing down the pathogenic progression of AD, while the epidemiological reports on its biological effect remains controversial. Considering this fact, the choice of drug that could maintain cholesterol homeostasis without altering its biosynthesis may yield a better therapeutic efficacy on AD. Thus, the present study focused on determining the influence of cholesterol and isoprenoids on amyloidogenic-cleavage of AβPP, in addition to resveratrol as a potent therapeutic drug in CHO-APPswe cell lines. High levels of cholesterol were found to enhance the maturation of AβPP and altered the expression and subcellular localization of ADAM10, BACE1, and PS1 thereby promoting Aβ generation, whereas high isoprenoids increased both maturation as well as amyloidogenic-cleavage of AβPP, which was evident through β-CTF production. Interestingly, the therapeutic efficacy of resveratrol maintained cholesterol homeostasis and reduced the amyloidogenic burden through its ability to enhance SIRT1 expression and thereby regulating differential expression of AD determinants.
authors.affiliation: Molecular Gerontology Laboratory, Department of Biochemistry, Bharathidasan University, Tiruchirappalli, Tamilnadu, India.
authors.forename: Mohan
authors.initials: M
authors.lastname: Sathya
authors.affiliation: Molecular Gerontology Laboratory, Department of Biochemistry, Bharathidasan University, Tiruchirappalli, Tamilnadu, India.
authors.forename: Ponnusamy
authors.initials: P
authors.lastname: Moorthi
authors.affiliation: Molecular Gerontology Laboratory, Department of Biochemistry, Bharathidasan University, Tiruchirappalli, Tamilnadu, India.
authors.forename: Palanisamy
authors.initials: P
authors.lastname: Premkumar
authors.affiliation: UGC-Faculty Recharge Program (UGC-FRP), University Grant Commission, Laboratory of Stem Cells and Neurodegeneration, Department of Animal Science, Bharathidasan University, Tiruchirappalli, Tamilnadu, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Kandasamy
authors.affiliation: Department of Bioinformatics, Bharathidasan University, Tiruchirappalli, Tamilnadu, India.
authors.forename: Kesavan Swaminathan
authors.initials: KS
authors.lastname: Jayachandran
authors.affiliation: Molecular Gerontology Laboratory, Department of Biochemistry, Bharathidasan University, Tiruchirappalli, Tamilnadu, India.
authors.forename: Muthuswamy
authors.initials: M
authors.lastname: Anusuyadevi
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D016466:CHO Cells; D002784:Cholesterol / Q000378:metabolism*; D003412:Cricetulus; D010450:Endopeptidases; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010447:Peptide Hydrolases / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D013729:Terpenes / Q000378:metabolism*; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D008565:Membrane Proteins; D013267:Stilbenes; D013729:Terpenes; D002784:Cholesterol; C475154:APH1A protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D000072197:ADAM10 Protein; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Alzheimer’s disease determinants; SIRT1; amyloid-β protein precursor; cholesterol; farnesyl pyrophosphate; geranyl geranyl pyrophosphate; resveratrol