摘要
我们先前报道了当阿尔茨海默病人接触到双氧水(H2O2)诱导的氧化应激和曾患有皮肤癌病人细胞凋亡的耐药性增加时,使其淋巴细胞死亡的易感性增强。这与我们提出的解释观察到的流行病学研究的负相关假设一致,阿尔茨海默病和癌症在相反方向解除了对细胞死亡机制的控制。在此我们调查了是否观察到的易感性增强与痴呆严重程度相关。采用临床痴呆评定量表(CDR)把23例AD病人分为严重痴呆组(CDR 3, n=10)和 轻中度痴呆组(CDR 1- 2, n=13)及15例健康对照组(HC) (CDR 0);来自这23例AD病人的外周血淋巴细胞接触双氧水20个小时。采用流式细胞术和碘化物染色法测定淋巴细胞凋亡数。观察到被双氧水诱导的来自严重痴呆病人的淋巴细胞凋亡易感性最强;然而与健康对照组相比,那些轻中度痴呆组细胞的易感性显示出中间值。我们发现AD病人的细胞凋亡或坏死率明显增加。多聚腺苷二磷酸核糖聚合酶-1(PARP-1) 抑制剂对H2O2 诱导的淋巴细胞凋亡有明显的保护作用;然而对痴呆严重的AD病人观察到较弱的保护作用。此外观察到PARP-1抑制剂对三组病人的凋亡或坏死率却不存在差异性。这些结果支持AD是系统性紊乱的见解。因此,H2O2 诱导的外周血淋巴细胞易感性增强与痴呆严重性相关,AD病人中的细胞凋亡增加是由于PARP依赖性细胞凋亡率/坏死率的增加。
关键词: 老年痴呆症,凋亡,痴呆,坏死,PARP依赖性细胞死亡,外周血淋巴细胞
Current Alzheimer Research
Title:Increased Susceptibility to Oxidative Death of Lymphocytes from Alzheimer Patients Correlates with Dementia Severity
Volume: 11 Issue: 9
Author(s): Daniela P. Ponce, Felipe Salech, Carol D. SanMartin, Monica Silva, Chengjie Xiong, Catherine M. Roe, Mauricio Henriquez, Andrew F. Quest and Maria I. Behrens
Affiliation:
关键词: 老年痴呆症,凋亡,痴呆,坏死,PARP依赖性细胞死亡,外周血淋巴细胞
摘要: We previously reported on enhanced susceptibility to death of lymphocytes from Alzheimer’s disease (AD) patients when exposed to hydrogen peroxide (H2O2)-induced oxidative stress and an increased resistance to death in those of patients with a history of skin cancer. This is consistent with our hypothesis proposing that the cellular machinery controlling cell death is deregulated in opposite directions in Alzheimer’s disease (AD) and cancer, to explain the inverse association observed in epidemiological studies. Here we investigated whether the observed increased susceptibility correlates with the degree of dementia severity. Peripheral lymphocytes from 23 AD patients, classified using the Clinical Dementia Rating (CDR) into severe dementia (CDR 3, n=10) and mild-to-moderate dementia (CDR 1- 2, n=13), and 15 healthy controls (HC) (CDR 0), were exposed to H2O2 for 20 hours. Lymphocyte death was determined by flow cytometry and propidium iodide staining. The greatest susceptibility to H2O2-induced death was observed for lymphocytes from severe dementia patients, whereas those with mild-to-moderate dementia exhibited intermediate values, compared to healthy controls. A significant increase in the apoptosis/necrosis ratio was found in AD patients. Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibition significantly protected from H2O2-induced death of lymphocytes, whereby a lower degree of protection was observed in severe AD patients. Moreover, inhibition of PARP-1 abolished the differences in apoptosis/necrosis ratios observed between the three groups of patients. These results support the notion that AD is a systemic disorder, whereby enhanced susceptibility to H2O2-induced death in peripheral lymphocytes correlates with dementia severity and enhanced death in AD patients is attributable to a PARP-dependent increase in the apoptosis/necrosis ratio.
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Cite this article as:
Ponce P. Daniela, Salech Felipe, SanMartin D. Carol, Silva Monica, Xiong Chengjie, Roe M. Catherine, Henriquez Mauricio, Quest F. Andrew and Behrens I. Maria, Increased Susceptibility to Oxidative Death of Lymphocytes from Alzheimer Patients Correlates with Dementia Severity, Current Alzheimer Research 2014; 11 (9) . https://dx.doi.org/10.2174/1567205011666141001113135
DOI https://dx.doi.org/10.2174/1567205011666141001113135 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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