Love S, Barber R, Wilcock G K
Department of Neuropathology, Frenchay Hospital, Bristol, UK.
Brain. 1999 Feb;122 ( Pt 2):247-53. doi: 10.1093/brain/122.2.247.
Experimental studies indicate that overactivation of the DNA repair protein poly(ADP-ribose) polymerase (PARP) in response to oxidative damage to DNA can cause cell death due to depletion of NAD+. Oxidative damage to DNA and other macromolecules has been reported to be increased in the brains of patients with Alzheimer's disease. In the present study we sought evidence of PARP activation in Alzheimer's disease by immunostaining sections of frontal and temporal lobe from autopsy material of 20 patients and 10 controls, both for PARP itself and for its end-product, poly(ADP-ribose). All of the brains had previously been subjected to detailed neuropathological examination to confirm the diagnosis of Alzheimer's disease or, in the controls, to exclude Alzheimer's disease-type pathology. Double immunolabelling for poly(ADP-ribose) and microtubule-associated protein 2 (MAP2), glial fibrillary-acidic protein (GFAP), CD68, A beta-protein or tau was used to assess the identity of the cells with poly(ADP-ribose) accumulation and their relationship to plaques and neurofibrillary tangles. Both PARP- and poly(ADP-ribose)-immunolabelled cells were detected in a much higher proportion of Alzheimer's disease (20 out of 20) brains than of control brains (5 out of 10) (P = 0.0018). Double-immunolabelling for poly(ADP-ribose) and markers of neuronal, astrocytic and microglial differentiation (MAP2, GFAP and CD68, respectively) showed many of the cells containing poly(ADP-ribose) to be neurons. Most of these were small pyramidal neurons in cortical laminae 3 and 5. A few of the cells containing poly(ADP-ribose) were astrocytes. No poly(ADP-ribose) accumulation was detected in microglia. Double-immunolabelling for poly(ADP-ribose) and tau or A beta-protein indicated that the cells with accumulation of poly(ADP-ribose) did not contain tangles and relatively few occurred within plaques. Our findings indicate that there is enhanced PARP activity in Alzheimer's disease and suggest that pharmacological interventions aimed at inhibiting PARP may have a role in slowing the progression of the disease.
实验研究表明，DNA修复蛋白聚（ADP - 核糖）聚合酶（PARP）因DNA氧化损伤而过度激活，可导致细胞因NAD +耗竭而死亡。据报道，阿尔茨海默病患者大脑中DNA和其他大分子的氧化损伤有所增加。在本研究中，我们通过对20例患者和10例对照的尸检材料的额叶和颞叶切片进行免疫染色，寻找阿尔茨海默病中PARP激活的证据，检测对象包括PARP本身及其终产物聚（ADP - 核糖）。所有大脑此前均经过详细的神经病理学检查，以确诊阿尔茨海默病，或在对照中排除阿尔茨海默病类型的病理学特征。采用聚（ADP - 核糖）与微管相关蛋白2（MAP2）、胶质纤维酸性蛋白（GFAP）、CD68、β - 淀粉样蛋白或tau蛋白的双重免疫标记，以评估聚（ADP - 核糖）积累细胞的身份及其与斑块和神经原纤维缠结的关系。与对照大脑（10例中有5例）相比，在阿尔茨海默病大脑（20例中有20例）中检测到PARP和聚（ADP - 核糖）免疫标记细胞的比例要高得多（P = 0.0018）。聚（ADP - 核糖）与神经元、星形胶质细胞和小胶质细胞分化标记（分别为MAP2、GFAP和CD68）的双重免疫标记显示，许多含有聚（ADP - 核糖）的细胞为神经元。其中大多数是皮质第3和第5层的小型锥体细胞。少数含有聚（ADP - 核糖）的细胞是星形胶质细胞。在小胶质细胞中未检测到聚（ADP - 核糖）积累。聚（ADP - 核糖）与tau蛋白或β - 淀粉样蛋白的双重免疫标记表明，聚（ADP - 核糖）积累的细胞不含缠结，且在斑块内出现的相对较少。我们的研究结果表明，阿尔茨海默病中PARP活性增强，提示旨在抑制PARP的药物干预可能在减缓疾病进展中发挥作用。
