title: ADAM10 expression and promoter haplotype in Alzheimer's disease.
abstract: Alzheimer's disease is confirmed at autopsy according to the accumulation of brain neuritic plaques and neurofibrillary tangles in the brain. Neuritic plaques contain amyloid-β (Aβ) and lower levels of Aβ correspond to an increase in ADAM10 α-secretase activity. ADAM10 α-secretase activity produces a soluble amyloid precursor protein (APP) alpha (sAPPα) product and negates the pathological production of Aβ. In this investigation, it was hypothesized that genetic variation with the ADAM10 promoter is associated with ADAM10 expression levels as well as cerebrospinal fluid sAPPα levels. Results from this investigation suggest that the ADAM10 rs514049-rs653765 C-A promoter haplotype is associated with: (1) higher CSF sAPPα levels in cognitively normal controls compared with Alzheimer's disease (AD) patients, (2) higher postmortem brain hippocampus, but not cerebellum, ADAM10 protein levels in subjects with low plaque scores compared with those with high plaque scores, and (3) higher promoter activity for promoter-only reporter constructs compared with promoter 3' untranslated region (3'UTR) constructs in the human neuroblastoma SHSY5Y cell line, but not in HepG2 or U118 cell lines. Taken together, these findings suggest that ADAM10 expression is modulated according to a promoter haplotype that is influenced in a brain region- and cell type-specific manner.
authors.affiliation: Geriatric Research, Education, and Clinical Center (GRECC), VA Puget Sound Health Care System, Seattle, WA, USA. lbekris@u.washington.edu
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Bekris
authors.forename: Franziska
authors.initials: F
authors.lastname: Lutz
authors.forename: Gail
authors.initials: G
authors.lastname: Li
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Galasko
authors.forename: Martin R
authors.initials: MR
authors.lastname: Farlow
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Quinn
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kaye
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Peskind
authors.forename: Chang-En
authors.initials: CE
authors.lastname: Yu
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000072197:ADAM10 Protein; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid; D000704:Analysis of Variance; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009447:Neuroblastoma / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human