Inverse association of Pin1 and tau accumulation in Alzheimer's disease hippocampus
Inverse association of Pin1 and tau accumulation in Alzheimer's disease hippocampus
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DOI：
10.1007/s00401-002-0581-1
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发表时间：
2002-11-01
影响因子：
12.7
通讯作者：
Arendt, T
中科院分区：
文献类型：
--
作者：
Holzer, M;Gärtner, U;Arendt, T
神经退行性变是阿尔茨海默病的病理标志之一，并不是在所有脑区或神经元中普遍存在。虽然内嗅皮层、海马和新皮层锥体神经元的脆弱性很高，但其他大脑结构基本上幸免于难。即使在高度脆弱的区域，如海马体，神经元也受到不同程度的影响。这种选择性易感性的分子基础仍然未知。神经退行性变涉及tau蛋白的过度磷酸化，这严重损害了其与微管的结合能力，因此被认为破坏了轴突细胞骨架。最近，Lit等人[Nature（1999）399：784]描述了肽基-脯氨酰顺反异构酶Pin 1恢复磷酸化tau的微管结合亲和力和微管稳定的能力。在本研究中，我们分析了潜在的参与Pin 1在选择性的脆弱性海马神经元的神经退行性疾病在阿尔茨海默氏病。Pin 1免疫反应以胞浆颗粒的形式出现，影响程度不同（CA 2>下托> CA 1> CA 3/CA 4）。由于颗粒空泡变性的主要标志物不共同标记Pin 1免疫反应颗粒，我们认为这些颗粒可能代表阿尔茨海默病的新病变。含有Pin 1颗粒的神经元没有神经元缠结。Pin 1的颗粒积聚可能对应于这些细胞中没有神经元病变，并且可能与神经元变性的其他机制相关。
Neurofibrillary degeneration, one of the pathological hallmarks of Alzheimer's disease, is not ubiquitous to all brain regions or neurons. While a high degree of vulnerability has been documented for entorhinal cortex, hippocampal and neocortical pyramidal neurons other brain structures are largely spared. Even within highly vulnerable regions such as hippocampus neurons are affected to a variable extent. The molecular basis for this selective susceptibility remains unknown. Neurofibrillary degeneration involves hyperphosphorylation of tau which critically impairs its binding capacity to microtubule and, therefore, is believed to disrupt the axonal cytoskeleton. Recently, Lit et al. [Nature (1999) 399:784] described the ability of the peptidyl-prolyl cis-trans isomerase Pin1 to recover microtubule-binding affinity and microtubule stabilisation of phosphorylated tau. In the present study, we analysed the potential involvement of Pin1 in selective vulnerability of hippocampal neurons to neurofibrillary degeneration in Alzheimer's disease. Pin1 immunoreactivity appeared as cytoplasmic granules affecting hippocampal subfields to a different extent (CA2>subiculum>CA1>CA3/CA4). Since the main markers of granulovacuolar degeneration do not co-label Pin1-immunoreactive granules, we propose that these granules may represent a new lesion in Alzheimer's disease. Neurons containing Pin1 granules were devoid of neurofibrillary tangles. Granular accumulation of Pin1 may correspond to an absence of neurofibrillary lesions in these cells and might be associated with other mechanisms of neuronal degeneration.