Age- and region-dependent alterations in Aβ-degrading enzymes:: implications for Aβ-induced disorders
Age- and region-dependent alterations in Aβ-degrading enzymes:: implications for Aβ-induced disorders
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DOI：
10.1016/j.neurobiolaging.2004.06.013
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发表时间：
2005-05-01
影响因子：
4.2
通讯作者：
LaFerla, FA
中科院分区：
文献类型：
--
作者：
Caccamo, A;Oddo, S;LaFerla, FA
淀粉样β-蛋白（Abeta）的积累是某些人脑疾病（如阿尔茨海默病（AD）和唐氏综合征）以及骨骼肌疾病包涵体肌炎（IBM）的基本特征。新出现的证据表明，Abeta的稳态水平是由生产和降解之间的平衡决定的。尽管导致Abeta形成的蛋白水解过程已得到广泛研究，但对降解Abeta的蛋白酶（包括胰岛素降解酶（IDE）和脑啡肽溶酶（NEP））知之甚少。在这里，我们测量了这些蛋白酶的稳态水平作为小鼠和人类的年龄和大脑/肌肉区域的函数。在易受AD病理影响的海马中，IDE和NEP稳态水平随年龄而降低。相比之下，在小脑中，一个没有显著Abeta积累的大脑区域，NEP和IDE水平在衰老过程中增加或保持不变。此外，IDE和NEP的稳态水平在小脑中显著高于皮质和海马。我们进一步表明，与AD患者的小脑相比，IDE在海马中的氧化程度更高。在肌肉中，我们发现快肌纤维和慢肌纤维的IDE和NEP水平不同，并且随着年龄的增长而变化。这些研究结果表明，年龄和区域特异性的变化，蛋白水解清除的Abeta代表一个关键的致病机制，可能占AD和IBM的特定大脑或肌肉区域的易感性。(C)2004爱思唯尔公司All rights reserved.
Accumulation of amyloid beta-protein (Abeta) is a fundamental feature of certain human brain disorders such as Alzheimer's disease (AD) and Down syndrome and also of the skeletal muscle disorder inclusion body myositis (IBM). Emerging evidence suggests that the steady-state levels of Abeta are determined by the balance between production and degradation. Although the proteolytic processes leading to Abeta formation have been extensively studied, less is known about the proteases that degrade Abeta, which include insulin-degrading enzyme (IDE) and neprilysin (NEP). Here we measured the steady-state levels of these proteases as a function of age and brain/muscle region in mice and humans. In the hippocampus, which is vulnerable to AD pathology, IDE and NEP steady-state levels diminish as function of age. By contrast, in the cerebellum, a brain region not marked by significant Abeta accumulation, NEP and IDE levels either increase or remain unaltered during aging. Moreover, the steady-state levels of IDE and NEP are significantly higher in the cerebellum compared to the cortex and hippocampus. We further show that IDE is more oxidized in the hippocampus compared to the cerebellum of AD patients. In muscle, we find differential levels of IDE and NEP in fast versus slow twitch muscle fibers that varies with aging. These findings suggest that age- and region-specific changes in the proteolytic clearance of Abeta represent a critical pathogenic mechanism that may account for the susceptibility of particular brain or muscle regions in AD and IBM. (C) 2004 Elsevier Inc. All rights reserved.