摘要
21号三体染色体和继之的淀粉样前体蛋白(APP)基因的额外复制以及增长的β-淀粉样蛋白(Aβ)肽的生成物是阿尔茨海默病(AD)发展和具有高风险阿尔茨海默病(AD)痴呆的唐氏综合症(DS) 患者的普遍病理基础。21-三体和其他形式的非整倍性在散发性和家族性阿尔茨海默病患者以及老鼠和细胞模型的神经元和外周细胞中也会出现,加强了AD和DS是同一事物的两个方面的结论。AD患者90%的神经退化可以归因于非整倍体神经元的选择性损失而使疾病产生,指示了非整倍性是导致神经细胞群的损耗的致病途径的基本特征。21-三体镶嵌现象也出现在C1型尼曼-皮克病患者和家族性或散发性的额颞叶大叶性变性(FTLD)患者的神经元和其他细胞以及相应的老鼠和细胞模型里。生化研究表明,Aβ通过抑制有丝分裂所需的特定的微管马达,诱导了培养细胞的有丝分裂纺锤体的缺陷、染色体的错误分离和非整倍性。这些数据表明,神经元的21-三体和其他类型的非整倍性的特征可能导致多种神经退行性疾病,也是其治疗干预的有效的部位。例如,减少细胞外钙或用氯化锂(LiCl)处理细胞阻断通过Aβ诱导的21-三体,后者的研究发现与近期用氯化锂治疗的双相患者呈低风险的痴呆和AD患者认知功能的建立的报告相关。
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Current Alzheimer Research
Title:Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer’s Disease
Volume: 13 Issue: 1
Author(s): Huntington Potter, Antoneta Granic and Julbert Caneus
Affiliation:
关键词:
摘要: Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer’s disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons and other cells from patients with Niemann-Pick C1 disease and from patients with familial or sporadic frontotemporal lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that Aβ induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention. For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy 21 by Aβ. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated with LiCl and in the stabilization of cognition in AD patients treated with LiCl.
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Huntington Potter, Antoneta Granic and Julbert Caneus , Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer’s Disease, Current Alzheimer Research 2016; 13 (1) . https://dx.doi.org/10.2174/156720501301151207100616
DOI https://dx.doi.org/10.2174/156720501301151207100616 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
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