Cataldo A M, Hamilton D J, Barnett J L, Paskevich P A, Nixon R A
Laboratories for Molecular Neuroscience, McLean Hospital, Belmont, Massachusetts, USA.
J Neurosci. 1996 Jan;16(1):186-99. doi: 10.1523/JNEUROSCI.16-01-00186.1996.
Specific antibodies and cytochemical markers combined with several imaging and morphometric techniques were used to characterize the endosomal-lysosomal system in mature neurons of the normal human central nervous system and to quantitate changes in its function in Alzheimer's disease. Compartments containing cathespin D (Cat D) and other acid hydrolases included a major subpopulation of mature lysosomes lacking mannose-6-phosphate receptors (MPR) and smaller populations of late endosomes (MPR-positive) and lipofuscin granules (MPR-negative). Antibodies to the pro-isoform of Cat D decorated perinuclear vacuolar compartments corresponding to late endosomes. Neurons and glia contained lysosomes with differing complements of acid hydrolases, implying different processing capabilities. Endosome/lysosome number per unit volume of cytoplasm was relatively well conserved within populations of normal neurons. By contrast, in morphometric analyses of Alzheimer's disease brains, 80-93% of pyramidal cells in the prefrontal cortex (laminae III or V) and hippocampus (CA2, CA3) displayed two- to eightfold higher numbers of hydrolase-positive vacuolar compartments than did corresponding cell populations in age-matched normal brains. Only 5-10% of cerebellar Purkinje cells, a less vulnerable population, showed the same statistically significant elevations. Most affected in these brain regions and in subcortical areas seemed otherwise normal by conventional histological staining and ultrastructural inspection. That both lysosomal and pro-Cat D- and MPR-positive endosomal compartments increased in number demonstrates that the endosomal-lysosomal system is activated markedly in vulnerable neuronal populations of Alzheimer's disease brains and implies that endocytosis or autophagy or both are accelerated persistently at an early stage of cellular compromise, greatly surpassing the degree of activity associated with normal aging. Early activation of the endosomal-lysosomal system represents a biological event potentially linking major etiological factors in Alzheimer's disease, including defective membrane proteins, apolipoprotein E function, and altered amyloid precursor protein processing.
特异性抗体和细胞化学标志物与多种成像和形态测量技术相结合，用于表征正常人类中枢神经系统成熟神经元中的内体-溶酶体系统，并定量其在阿尔茨海默病中的功能变化。含有组织蛋白酶D（Cat D）和其他酸性水解酶的区室包括主要的缺乏甘露糖-6-磷酸受体（MPR）的成熟溶酶体亚群，以及较小的晚期内体（MPR阳性）和脂褐素颗粒（MPR阴性）群体。针对Cat D前体同工型的抗体标记了对应于晚期内体的核周空泡区室。神经元和神经胶质细胞含有具有不同酸性水解酶组成的溶酶体，这意味着不同的加工能力。在正常神经元群体中，每单位体积细胞质中的内体/溶酶体数量相对保持稳定。相比之下，在对阿尔茨海默病大脑的形态测量分析中，前额叶皮质（III或V层）和海马体（CA2、CA3）中80%-93%的锥体细胞显示出水解酶阳性空泡区室的数量比年龄匹配的正常大脑中的相应细胞群体高出2至8倍。只有5%-10%的小脑浦肯野细胞（一个较不易受影响的群体）显示出相同的统计学显著升高。通过传统组织学染色和超微结构检查，这些脑区和皮质下区域的大多数在其他方面似乎正常。溶酶体以及前体Cat D和MPR阳性内体区室的数量均增加，这表明在阿尔茨海默病大脑的易损神经元群体中，内体-溶酶体系统被显著激活，这意味着在细胞受损的早期阶段，内吞作用或自噬作用或两者都持续加速，大大超过了与正常衰老相关的活动程度。内体-溶酶体系统的早期激活代表了一个可能将阿尔茨海默病的主要病因因素联系起来的生物学事件，这些因素包括膜蛋白缺陷、载脂蛋白E功能以及淀粉样前体蛋白加工改变。
