Neuronal apoptosis and autophagy cross talk in aging PS/APP mice, a model of Alzheimer's disease.
Neuronal apoptosis and autophagy cross talk in aging PS/APP mice, a model of Alzheimer's disease.
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DOI：
10.2353/ajpath.2008.071176
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发表时间：
2008-09
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影响因子：
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通讯作者：
Dun-Sheng Yang;Asok Kumar;Philip H. Stavrides;J. Peterson;Corrine M Peterhoff;M. Pawlik;E. Levy;A. Cataldo;R. Nixon
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文献类型：
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作者：
Dun-Sheng Yang;Asok Kumar;Philip H. Stavrides;J. Peterson;Corrine M Peterhoff;M. Pawlik;E. Levy;A. Cataldo;R. Nixon
阿尔茨海默病（AD）中神经元丧失的机制尚不清楚。在模拟ad样神经变性的PS/APP小鼠中，细胞凋亡是神经元细胞死亡的主要形式。成年PS/APP小鼠的缩缩神经元发生凋亡变化，包括DNA断裂、caspase-3激活和caspase-cleaved α -spectrin的产生，与野生型小鼠的发育性神经元凋亡相同。免疫金细胞化学超微结构检查证实，活化的caspase-3阳性神经元也表现出染色质边缘和凝聚、染色质球和核膜断裂。与年龄匹配的对照组相比，PS/APP小鼠皮质和海马的凋亡谱数量在6月龄时增加了2至3倍，在21至26月龄时增加了8倍。其他经历暗细胞变性的神经元没有表现出这些凋亡特征。活化的caspase-3和caspase-3-cleaved spectrin在自噬空泡中丰富，在PS/APP小鼠类似AD脑的营养不良神经突中积累。给药半胱氨酸蛋白酶抑制剂lepeptin可促进PS/APP小鼠轴突中含有活化caspase-3的自噬空泡的积累，在较小程度上也可促进野生型小鼠轴突中含有活化caspase-3的自噬空泡的积累，这表明这种促凋亡因子可通过自噬降解。leupeptin诱导的自噬损伤增加了PS/APP小鼠凋亡神经元的数量。我们的研究结果证实了凋亡是衰老PS/APP小鼠神经元细胞死亡的一种模式，并确定了自噬和凋亡之间的串扰，影响ad相关神经退行性变中神经元的存活。
Mechanisms of neuronal loss in Alzheimer's disease (AD) are poorly understood. Here we show that apoptosis is a major form of neuronal cell death in PS/APP mice modeling AD-like neurodegeneration. Pyknotic neurons in adult PS/APP mice exhibited apoptotic changes, including DNA fragmentation, caspase-3 activation, and caspase-cleaved alpha-spectrin generation, identical to developmental neuronal apoptosis in wild-type mice. Ultrastructural examination using immunogold cytochemistry confirmed that activated caspase-3-positive neurons also exhibited chromatin margination and condensation, chromatin balls, and nuclear membrane fragmentation. Numbers of apoptotic profiles in both cortex and hippocampus of PS/APP mice compared with age-matched controls were twofold to threefold higher at 6 months of age and eightfold higher at 21 to 26 months of age. Additional neurons undergoing dark cell degeneration exhibited none of these apoptotic features. Activated caspase-3 and caspase-3-cleaved spectrin were abundant in autophagic vacuoles, accumulating in dystrophic neurites of PS/APP mice similar to AD brains. Administration of the cysteine protease inhibitor, leupeptin, promoted accumulation of autophagic vacuoles containing activated caspase-3 in axons of PS/APP mice and, to a lesser extent, in those of wild-type mice, implying that this pro-apoptotic factor is degraded by autophagy. Leupeptin-induced autophagic impairment increased the number of apoptotic neurons in PS/APP mice. Our findings establish apoptosis as a mode of neuronal cell death in aging PS/APP mice and identify the cross talk between autophagy and apoptosis, which influences neuronal survival in AD-related neurodegeneration.