Understanding molecular mechanisms of proteolysis in Alzheimer's disease: Progress toward therapeutic interventions
Understanding molecular mechanisms of proteolysis in Alzheimer's disease: Progress toward therapeutic interventions
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DOI：
10.1016/j.bbapap.2005.02.013
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发表时间：
2005-08-01
影响因子：
3.2
通讯作者：
Saido, TC
中科院分区：
文献类型：
--
作者：
Higuchi, M;Iwata, N;Saido, TC
淀粉样β蛋白(Aβ)不仅是阿尔茨海默病(AD)脑内细胞外纤维病变的主要成分，而且在神经元中也是生理性产生和代谢的。这一事实使我们认为，与年龄相关的Aβ分解代谢的减少可能有助于AD的分子发病机制，为寻找在大脑中降解A的蛋白水解酶提供了理论基础。我们最近的研究表明，neprilysin是体内最有效的Aβ降解酶。内源性neprilysin缺乏以基因剂量依赖的方式提高了neprilysin基因敲除小鼠大脑中的A[水平，并且在小鼠大脑的几个区域出现了与年龄相关的neprilysin的下降。这些相同区域的神经病理变化与AD患者在疾病早期的认知障碍有关。此外，在AD患者的海马区和颞叶皮质中，neprilysin的mRNA水平也被发现显著和选择性地降低。Neprilysin活性降低在AD发病机制中的作用已被阐明，neprilysin上调作为一种新的AD预防和治疗方法的可能性已经打开。由于Neprilysin的表达水平和活性可能受神经肽及其受体的调节，这些受体的非肽类激动剂可能是维持老年人脑内足够水平的Aβ分解代谢的有效药物。除了Aβ沉积外，神经细胞内的纤维损害，如神经原纤维缠结，也是AD的一个病理标志，由此导致的细胞骨架破坏的程度可能取决于蛋白水解酶的活性水平。在主要细胞骨架成分为良好底物的蛋白酶中，在我们最近使用基因工程小鼠进行的分析中，Calain被证明参与了兴奋性毒性应激诱导的神经元性变性。此外，我们发现，这种病理可以通过控制一种内源性钙蛋白酶抑制剂的活性来减少，这为包括阿尔茨海默病在内的各种神经退行性疾病的治疗提供了一种可能的方法。(C)2005 Elsevier B.V.保留所有权利。
Amyloid beta peptide (A beta) is not only a major constituent of extracellular fibrillary pathologies in Alzheimer's disease (AD) brains, but is also physiologically produced and metabolized in neurons. This fact led us to the notion that an age-related decrease in A beta catabolism may contribute to the molecular pathogenesis of AD, providing a rationale for seeking proteolytic enzymes that degrade A in the brain. Our recent studies have demonstrated,that neprilysin is the most potent A beta-degrading enzyme in vivo. Deficiency of endogenous neprilysin elevates the level of A[ in brains of neprilysin-knockout mice in a gene dose-dependent manner, and an age-associated decline of neprilysin occurs in several regions Of mouse brain. Neuropathological alterations in these same regions have been implicated in cognitive impairments of AD patients at an early stage of the disease. Furthermore, the level of neprilysin mRNA has been found to be significantly and selectively reduced in the hippocampus and temporal cortex of AD patients. A clarification of the role played by decreased neprilysin activity in the pathogenesis of AD has opened up,the possibility of neprilysin up-regulation as a novel preventive and therapeutic approach to AD. Since the expression level and activity of neprilysin are likely to be regulated by neuropeptides and their receptors, non-peptidic agonists for these receptors might be effective agents to maintain a sufficient level of A beta catabolism in brains of the elderly. In addition to A beta deposits, intraneuronal fibrillary lesions, such as neurofibrillary tangles, are also a pathological hallmark of AD, and the extent of the resultant cytoskeletal disruptions may be dependent upon the activity levels of proteolytic enzymes. Among proteases for which major cytoskeletal components are good substrates, calpains were shown to participate in excitotoxic stress-induced neuritic degeneration in our recent analysis using genetically engineered mice. Moreover, we have found that this pathology can be reduced by controlling the activity of an endogenous calpain inhibitor known as calpastatin, providing a possible approach for the treatment of diverse neurodegenerative disorders, including AD. (c) 2005 Elsevier B.V. All rights reserved.