مطالعه مقدماتی از بروز ژنوم پراکنده کامل و تک ژنی زودرس بیماری آلزایمر
|کد مقاله||سال انتشار||مقاله انگلیسی||ترجمه فارسی||تعداد کلمات|
|30814||2013||7 صفحه PDF||سفارش دهید||5784 کلمه|
Publisher : Elsevier - Science Direct (الزویر - ساینس دایرکت)
Journal : Neurobiology of Aging, Volume 34, Issue 7, July 2013, Pages 1772–1778
Alzheimer's disease (AD) is the most common neurodegenerative dementia. Approximately 10% of cases present at an age of onset before 65 years old, which in turn can be monogenic familial AD (FAD) or sporadic early-onset AD (sEOAD). Mutations in PSEN1, PSEN2, and APP genes have been linked with FAD. The aim of our study is to describe the brain whole-genome RNA expression profile of the posterior cingulate area in sEOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). Fourteen patients (7 sEOAD and 7 FAD-PSEN1) and 7 neurologically healthy control subjects were selected and whole-genome expression was measured using Affymetrix Human Gene 1.1 microarrays. We identified statistically significant expression changes in sEOAD and FAD-PSEN1 brains with respect to control subjects (3183 and 3350 differentially expressed genes [DEG] respectively, false discovery rate-corrected p < 0.05). Of them, 1916 DEG were common between the 2 comparisons. We did not identify DEG between sEOAD and FAD-PSEN1. Microarray data were validated through real-time quantitative polymerase chain reaction. In silico analysis of DEG revealed an alteration in biological pathways related to intracellular signaling pathways (particularly calcium signaling), neuroactive ligand-receptor interactions, axon guidance, and long-term potentiation in both groups of patients. In conclusion, the altered biological final pathways in sEOAD and FAD-PSEN1 are mainly related with cell signaling cascades, synaptic plasticity, and learning and memory processes. We hypothesize that these 2 groups of early-onset AD with distinct etiologies and likely different could present a neurodegenerative process with potential different pathways that might converge in a common and similar final stage of the disease.
Alzheimer's disease (AD) is the most frequent cause of neurodegenerative dementia, which leads to cognitive and behavioral impairments (McKhann et al., 1984 and McKhann et al., 2011). According to the age of onset of symptoms, AD can be arbitrarily divided in 2 groups: late-onset AD (LOAD) (onset ≥65 years old) (approximately 90% of cases) and early-onset AD (EOAD) (onset <65 years old) (approximately 10% of cases) (Koedam et al., 2010; van der Flier et al., 2011). Genetically, AD can be classified in 2 forms: (1) familial or monogenic forms of AD (FAD) (0.1%–0.5%), with an autosomal dominant pattern of inheritance, and early-onset AD caused by rare and highly penetrant mutations in 3 genes: the amyloid precursor protein gene (APP), the presenilin 1 gene (PSEN1), and the presenilin 2 gene (PSEN2); and (2) polygenic and/or multifactorial or so-called “sporadic” cases with less apparent or no familial aggregation and usually of later age at onset. After hundreds of association genetic studies and genome-wide association studies of thousands of patients with LOAD, different genes have been identified as risk factors, (http://www.alzgene.org/) ( Bertram et al., 2007), although only the presence of the allele ε4 of the apolipoprotein E gene (APOE) has been unequivocally established as a genetic risk factor for AD. AD can be clinically heterogeneous and the frequency of atypical clinical presentations is different between EOAD, FAD, and LOAD (Balasa et al., 2011; Gomez-Tortosa et al., 2010). However, the underlying neuropathological findings between them are similar, with extracellular deposition of amyloid-β peptide plaques, intracellular neurofibrillary tangles—that consist of hyperphosphorylated aggregates of the microtubule-associated protein tau—and selective neuronal loss (Braak and Braak, 1997). Microarray technology allows the measurement of the expression of many thousands of genes simultaneously. There are multiple array-based choices for surveying genome-wide gene expression that differ in content, probe preparation methods, and chemistry of the array. During the past decade many studies have investigated human gene expression changes in AD, mainly in brain tissue (Avramopoulos et al., 2011; Blalock et al., 2004 and Blalock et al., 2011; Booij et al., 2011; Colangelo et al., 2002; Dunckley et al., 2006; Emilsson et al., 2006; Ginsberg et al., 2000; Grunblatt et al., 2007; Haroutunian et al., 2009; Katsel et al., 2009; Liang et al., 2008 and Liang et al., 2010; Loring et al., 2001; Lukiw and Crapper McLachlan, 1990; Parachikova et al., 2007; Pasinetti, 2001; Podtelezhnikov et al., 2011; Ray et al., 2008; Ricciarelli et al., 2004; Yao et al., 2003). Data obtained until now have yielded important new insights into the possible disease mechanisms and consequences of the disease at the molecular level. Multiple processes have been implicated in AD, notably including biological pathways related to synaptic function and neurotransmission, signal transduction, energy metabolism, oxidative stress, calcium signaling, and cytoskeleton protein processing or misfolding, inflammation, and cholesterol synthesis (Blalock et al., 2004; Emilsson et al., 2006; Simpson et al., 2011). Nevertheless, all of these studies have been focused in sporadic LOAD, and to our best knowledge, there are no studies on sporadic EOAD (sEOAD) or FAD. The aim of this study is to define the brain differential gene expression profile in 2 different groups of EOAD patients, sEOAD and genetically determined FAD caused by PSEN1 mutations (FAD-PSEN1), with respect to control subjects. We also wanted to find possible differences between them to infer if distinct pathological cascades are implicated in the pathogenesis of sEOAD and FAD.