ADAM10 expression and promoter haplotype in Alzheimer's disease

NEUROBIOLOGY OF AGING

卷:33

Article

Bekris, Lynn M.^1,2  Lutz, Franziska²  Galasko, Douglas R.^4,5  Farlow, Martin R.⁶  Quinn, Joseph F.^7,8  Kaye, Jeffrey A.^7,8  Leverenz, James B.^3,9,10  Tsuang, Debby W.²  Montine, Thomas J.¹¹  Yu, Chang-En² 

[1] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98108 USA

[2] VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA

[3] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA

[4] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA

[5] VA Med Ctr San Diego, San Diego, CA USA

[6] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN USA

[7] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA

[8] Portland VA Med Ctr, Portland, OR USA

[9] VA Puget Sound Hlth Care Syst, MIRECC, NW Network VISN 20, Seattle, WA USA

[10] Parkinsons Dis Res Educ & Clin Ctr PADRECC, NW Network VISN 20, Philadelphia, PA USA

[11] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

关键词: ADAM10;    Haplotype;    sAPP alpha;    Alzheimer's disease;    Reporter assay;    Neuritic plaques;    Brain;    Hippocampus;    Cerebrospinal fluid;   

DOI  :  10.1016/j.neurobiolaging.2012.03.013

来源: Elsevier

【 摘 要 】

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-beta (A beta) and lower levels of A beta correspond to an increase in ADAM10 alpha-secretase activity. ADAM10 alpha-secretase activity produces a soluble amyloid precursor protein (APP) alpha (sAPP alpha) product and negates the pathological production of A beta. In this investigation, it was hypothesized that genetic variation with the ADAM10 promoter is associated with ADAM10 expression levels as well as cerebrospinal fluid sAPP alpha levels. Results from this investigation suggest that the ADAM10 rs514049-rs653765 C-A promoter haplotype is associated with: (1) higher CSF sAPP alpha 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. (C) 2012 Elsevier Inc. All rights reserved.

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