بروز ADAM10 و هاپلوتیپ پروموتر در بیماری آلزایمر
|کد مقاله||سال انتشار||مقاله انگلیسی||ترجمه فارسی||تعداد کلمات|
|30788||2012||9 صفحه PDF||سفارش دهید||محاسبه نشده|
Publisher : Elsevier - Science Direct (الزویر - ساینس دایرکت)
Journal : Neurobiology of Aging, Volume 33, Issue 9, September 2012, Pages 2229.e1–2229.e9
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.
Amyloid-β (Aβ), processed from amyloid precursor protein (APP) by β- and γ-secretases, accumulates in the brain as Aβ-containing plaques (Selkoe, 1998); one form, called neuritic plaques, is most closely associated with Alzheimer's disease (AD). Alternatively, α-secretase cleavage within the β-amyloid domain negates the cleavage step that produces pathogenic Aβ (Selkoe, 1998). The membrane-bound disintegrin metalloproteinases (ADAMs) are capable of cleaving APP at the α-secretase site, with ADAM10 as the major α-secretase in the brain (Fahrenholz et al., 2000, Postina, 2008 and Postina, 2012). An increase in ADAM10 levels in a mouse model corresponds to a decrease in Aβ plaque levels (Postina et al., 2004). The genomic structure and function of the ADAM10 promoter has been described ( Prinzen et al., 2005). The 5' untranslated region (5'UTR) of ADAM10 has been reported to repress the rate of ADAM10 translation ( Lammich et al., 2010), and retinoic acid and acitretin stimulate promoter activity and increase ADAM10 levels in human cell lines and a mouse model ( Endres et al., 2005 and Tippmann et al., 2009). Genetic variation within the ADAM10 promoter has recently been associated with cerebrospinal fluid (CSF) soluble APPα (sAPPα) levels in AD patients compared with cognitively normal control subjects, implicating an important ADAM10 role in AD ( Bekris et al., 2011). ADAM10 mRNA has been reported to be high in AD patients ( Gatta et al., 2002), whereas ADAM10 protein levels have been reported to be low in CSF and platelets from AD patients ( Colciaghi et al., 2002, Colciaghi et al., 2004 and Tang et al., 2006). ADAM10 immunostaining has been reported to be reduced in AD brain ( Bernstein et al., 2009). Given the likely influence of ADAM10 expression levels on sAPPα levels in AD, it is important to further characterize the influence of ADAM10 promoter genetic variation on both transcription and translation (mRNA and protein) of ADAM10 in AD patients compared with cognitively normal control subjects. Because to our knowledge human brain ADAM10 mRNA and protein levels have not been previously measured in parallel in the same sample, and because an association between ADAM10 promoter genetic variation, ADAM10 expression, and neuritic plaque load have not been described, the aim of this investigation was to determine whether ADAM10 promoter genetic variation is associated with differential ADAM10 brain expression in subjects with a high neuritic plaque score compared with subjects with a low neuritic plaque score and CSF sAPPα levels.