Jellinger K A, Stadelmann C H
Ludwig Boltzmann Institute of Clinical Neurobiology, Vienna, Austria.
J Neural Transm Suppl. 2000(60):21-36. doi: 10.1007/978-3-7091-6301-6_2.
Progressive cell loss in specific neuronal populations is the pathological hallmark of neurodegenerative diseases, but its mechanisms remain unresolved. Apoptotic cell death has been implicated as a major mechanism in Alzheimer disease (AD), Parkinson disease (PD) and other neurodegenerative disorders. However, DNA fragmentation in human brain as a sign of neuronal cell injury is too frequent to account for the continuous loss in these slowly progressive diseases. In a series of autopsy confirmed cases of AD, PD, related disorders, and age-matched controls, DNA fragmentation using the TUNEL method, an array of apoptosis-related proteins (ARP), proto-oncogenes, and activated caspase-3, the key enzyme of late-stage apoptosis, were examined. In AD, a considerable number of hippocampal neurons and glial cells showed DNA fragmentation with a 3- to 6-fold increase related to neurofibrillary tangles and amyloid deposits, but only 1 in 2.600 to 5.600 neurons displayed apoptotic morphology and cytoplasmic immunoreactivity for activated caspase-3, whereas no neurons were labeled in age-matched controls. caspase-3 immunoreactivity was seen in granules of cells with granulovacuolar degeneration, in around 25% co-localized with early cytoplasmic deposition of tau-protein. In progressive supranuclear palsy, only single neurons and several oligodendrocytes in brainstem, some with tau-deposits, were TUNEL-positive and expressed both ARPs and activated caspase-3. In PD, dementia with Lewy bodies, multisystem atrophy (MSA), and corticobasal degeneration, TUNEL-positivity and expression of ARPs or activated caspase-3 were only seen in microglia and oligodendrocytes with cytoplasmic inclusions, but not in neurons. These data provide evidence for extremely rare apoptotic neuronal death in AD and PSP compatible with the progression of neuronal degeneration in these chronic diseases. Apoptosis mainly involves reactive microglia and oligodendroglia, the latter often involved by deposits of insoluble fibrillary proteins, while alternative mechanisms of neuronal death may occur. Susceptible cell populations in a proapoptotic environment show increased vulnerability towards metabolic or other noxious factors, with autophagy as a possible protective mechanism in early stages of programmed cell death. The intracellular cascade leading to cell death still awaits elucidation.
特定神经元群体中进行性细胞丢失是神经退行性疾病的病理标志，但其机制仍未得到解决。凋亡性细胞死亡被认为是阿尔茨海默病（AD）、帕金森病（PD）和其他神经退行性疾病的主要机制。然而，人脑中作为神经元细胞损伤标志的DNA片段化过于频繁，无法解释这些缓慢进展性疾病中细胞的持续丢失。在一系列经尸检证实的AD、PD、相关疾病以及年龄匹配对照的病例中，使用TUNEL法检测了DNA片段化、一系列凋亡相关蛋白（ARP）、原癌基因以及晚期凋亡关键酶活化的半胱天冬酶-3。在AD中，相当数量的海马神经元和胶质细胞显示出DNA片段化，与神经原纤维缠结和淀粉样沉积物相关的增加了3至6倍，但每2600至5600个神经元中只有1个显示出凋亡形态以及活化半胱天冬酶-3的细胞质免疫反应性，而在年龄匹配的对照中未发现神经元被标记。在具有颗粒空泡变性的细胞颗粒中可见半胱天冬酶-3免疫反应性，约25%与tau蛋白的早期细胞质沉积共定位。在进行性核上性麻痹中，脑干中只有单个神经元和几个少突胶质细胞呈TUNEL阳性，并同时表达ARP和活化的半胱天冬酶-3，其中一些有tau沉积物。在PD、路易体痴呆、多系统萎缩（MSA）和皮质基底节变性中，TUNEL阳性以及ARP或活化半胱天冬酶-3的表达仅见于有细胞质内含物的小胶质细胞和少突胶质细胞，而在神经元中未见。这些数据为AD和进行性核上性麻痹中极其罕见的凋亡性神经元死亡提供了证据，这与这些慢性疾病中神经元变性的进展相一致。凋亡主要涉及反应性小胶质细胞和少突胶质细胞，后者常被不溶性纤维状蛋白沉积物累及，而可能存在神经元死亡的其他机制。处于促凋亡环境中的易感细胞群体对代谢或其他有害因素的易损性增加，自噬可能是程序性细胞死亡早期阶段的一种保护机制。导致细胞死亡的细胞内级联反应仍有待阐明。
