Chen Ming, Nguyen Huey T
Aging Research Laboratory, Research and Development Service, Bay Pines Veterans Affairs Healthcare System Bay Pines, FL, USA ; Department of Molecular Pharmacology and Physiology, University of South Florida Tampa, FL, USA.
Aging Research Laboratory, Research and Development Service, Bay Pines Veterans Affairs Healthcare System Bay Pines, FL, USA.
Front Aging Neurosci. 2014 Dec 3;6:329. doi: 10.3389/fnagi.2014.00329. eCollection 2014.
Sporadic Alzheimer's disease (sAD) has not been explained by any current theories, so new hypotheses are urgently needed. We proposed that "energy and Ca(2+) signaling deficits" are perhaps the earliest modifiable defects in brain aging underlying memory decline and tau deposits (by means of inactivating Ca(2+)-dependent protease calpain). Consistent with this hypothesis, we now notice that at least eight other known calpain substrates have also been reported to accumulate in aging and AD. Thus, protein accumulation or aggregation is not a "pathogenic" event, but occurs naturally and selectively to a peculiar family of proteins, and is best explained by calpain inactivation. Why are only calpain substrates accumulated and how can they stay for decades in the brain without being attacked by many other non-specific proteases there? We believe that these long-lasting puzzles can be explained by calpain's unique properties, especially its unusual specificity and exclusivity in substrate recognition, which can protect the substrates from other proteases' attacks after calpain inactivation. Interestingly, our model, in essence, may also explain tau phosphorylation and the formation of amyloid plaques. Our studies suggest that α-secretase is an energy-/Ca(2+)-dual dependent protease and is also the primary determinant for Aβ levels. Therefore, β- and γ-secretases can only play secondary roles and, by biological laws, they are unlikely to be "positively identified". This study thus raises serious questions for policymakers and researchers and these questions may help explain why sAD can remain an enigma today.
散发性阿尔茨海默病（sAD）目前尚无任何理论能够解释，因此迫切需要新的假说。我们提出，“能量和Ca(2+)信号缺陷”可能是大脑衰老过程中最早可改变的缺陷，是记忆衰退和tau蛋白沉积的基础（通过使依赖Ca(2+)的蛋白酶钙蛋白酶失活）。与这一假说一致的是，我们现在注意到至少还有其他八种已知的钙蛋白酶底物也被报道在衰老和AD中积累。因此，蛋白质积累或聚集并非“致病”事件，而是自然且选择性地发生在一类特殊的蛋白质家族中，最好用钙蛋白酶失活来解释。为什么只有钙蛋白酶底物会积累，以及它们如何能在大脑中存留数十年而不被许多其他非特异性蛋白酶攻击？我们认为，这些长期存在的谜题可以用钙蛋白酶的独特特性来解释，尤其是其在底物识别方面不同寻常的特异性和排他性，这可以在钙蛋白酶失活后保护底物免受其他蛋白酶的攻击。有趣的是，我们的模型本质上或许也能解释tau蛋白磷酸化和淀粉样斑块的形成。我们的研究表明，α-分泌酶是一种能量/Ca(2+)双依赖蛋白酶，也是Aβ水平的主要决定因素。因此，β-和γ-分泌酶只能起次要作用，根据生物学规律，它们不太可能被“明确认定”。这项研究因此给政策制定者和研究人员提出了严峻的问题，这些问题或许有助于解释为什么sAD至今仍是一个谜。
