title: The amyloid precursor protein (APP) family members are key players in S-adenosylmethionine formation by MAT2A and modify BACE1 and PSEN1 gene expression-relevance for Alzheimer's disease.
abstract: Central hallmark of Alzheimer's disease are senile plaques mainly composed of β-amyloid, which is a cleavage product of the amyloid precursor protein (APP). The physiological function of APP and its family members APLP1 and APLP2 is poorly understood. In order to fill this gap, we established a cell-culture based model with simultaneous knockdown of all members of the family. A comprehensive proteome study of the APP/APLP1/APLP2 knockdown cell lysates versus controls revealed significant protein abundance changes of more than 30 proteins. Targeted validation of selected candidates by immunoblotting supported the significant down-regulation of the methionine adenosyltransferase II, alpha (MAT2A) as well as of peroxiredoxin 4 in the knockdown cells. Moreover, MAT2A was significantly down-regulated at the mRNA level as well. MAT2A catalyzes the production of S-adenosylmethionine from methionine and ATP, which plays a pivotal role in the methylation of neurotransmitters, DNA, proteins, and lipids. MAT2A-dependent significant up-regulation of S-adenosylmethionine was also detectable in the knockdown cells compared with controls. Our results point to a role of the APP family proteins in cellular methylation mechanisms and fit to findings of disturbed S-adenosylmethionine levels in tissue and CSF of Alzheimer disease patients versus controls. Importantly, methylation plays a central role for neurotransmitter generation like acetylcholine pointing to a crucial relevance of our findings for Alzheimer's disease. In addition, we identified differential gene expression of BACE1 and PSEN1 in the knockdown cells, which is possibly a consequence of MAT2A deregulation and may indicate a self regulatory mechanism.
authors.affiliation: Functional Proteomics, Medizinisches Proteom-Center, Ruhr-University Bochum, D-44801 Bochum, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schrötter
authors.forename: Kathy
authors.initials: K
authors.lastname: Pfeiffer
authors.forename: Fouzi
authors.initials: F
authors.lastname: El Magraoui
authors.forename: Harald W
authors.initials: HW
authors.lastname: Platta
authors.forename: Ralf
authors.initials: R
authors.lastname: Erdmann
authors.forename: Helmut E
authors.initials: HE
authors.lastname: Meyer
authors.forename: Rupert
authors.initials: R
authors.lastname: Egensperger
authors.forename: Katrin
authors.initials: K
authors.lastname: Marcus
authors.forename: Thorsten
authors.initials: T
authors.lastname: Müller
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008716:Methionine Adenosyltransferase / Q000378:metabolism*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D054464:Peroxiredoxins; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D020543:Proteome / Q000378:metabolism; D015203:Reproducibility of Results; D012436:S-Adenosylmethionine / Q000378:metabolism*; D013194:Staining and Labeling
chemical_list: C489697:APLP1 protein, human; C084104:APLP2 protein, human; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020543:Proteome; D012436:S-Adenosylmethionine; C515980:PRDX4 protein, human; D054464:Peroxiredoxins; C527161:MAT2A protein, human; D008716:Methionine Adenosyltransferase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human