ADAM10 expression and promoter haplotype in Alzheimer's disease

Lynn M. Bekris, Franziska Lutz, Gail Li, Douglas R. Galasko, Martin R. Farlow, Joseph Quinn, Jeffrey Kaye, James B. Leverenz, Debby W. Tsuang, Thomas J. Montine, Elaine R. Peskind, Chang En Yu

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
JournalNeurobiology of Aging
Volume33
Issue number9
DOIs
StatePublished - Sep 2012

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Haplotypes
Alzheimer Disease
Amyloid Precursor Protein Secretases
Amyloid Plaques
Brain
Cell Line
Neurofibrillary Tangles
Macrophage Colony-Stimulating Factor
Amyloid beta-Protein Precursor
3' Untranslated Regions
Neuroblastoma
Amyloid
Cerebellum
Cerebrospinal Fluid
Autopsy
Hippocampus

Keywords

  • ADAM10
  • Alzheimer's disease
  • Brain
  • Cerebrospinal fluid
  • Haplotype
  • Hippocampus
  • Neuritic plaques
  • Reporter assay
  • SAPPα

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

ADAM10 expression and promoter haplotype in Alzheimer's disease. / Bekris, Lynn M.; Lutz, Franziska; Li, Gail; Galasko, Douglas R.; Farlow, Martin R.; Quinn, Joseph; Kaye, Jeffrey; Leverenz, James B.; Tsuang, Debby W.; Montine, Thomas J.; Peskind, Elaine R.; Yu, Chang En.

In: Neurobiology of Aging, Vol. 33, No. 9, 09.2012.

Research output: Contribution to journalArticle

Bekris, LM, Lutz, F, Li, G, Galasko, DR, Farlow, MR, Quinn, J, Kaye, J, Leverenz, JB, Tsuang, DW, Montine, TJ, Peskind, ER & Yu, CE 2012, 'ADAM10 expression and promoter haplotype in Alzheimer's disease', Neurobiology of Aging, vol. 33, no. 9. https://doi.org/10.1016/j.neurobiolaging.2012.03.013
Bekris, Lynn M. ; Lutz, Franziska ; Li, Gail ; Galasko, Douglas R. ; Farlow, Martin R. ; Quinn, Joseph ; Kaye, Jeffrey ; Leverenz, James B. ; Tsuang, Debby W. ; Montine, Thomas J. ; Peskind, Elaine R. ; Yu, Chang En. / ADAM10 expression and promoter haplotype in Alzheimer's disease. In: Neurobiology of Aging. 2012 ; Vol. 33, No. 9.
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