Department of Psychiatry and Psychotherapy, Clinical Research Group, University Medical Centre Johannes Gutenberg-University Mainz, Untere Zahlbacher Str. 8, 55131 Mainz, Germany.
Exp Brain Res. 2012 Apr;217(3-4):343-52. doi: 10.1007/s00221-011-2885-7. Epub 2011 Oct 4.
The amyloid precursor protein (APP) has a pivotal role in pathogenesis of Alzheimer's disease (AD) via its beta- and gamma-secretase-derived cleavage products--the A-beta peptides. An alternative processing pathway provided by the alpha-secretase prevents formation of those toxic peptides and gives rise to the neurotrophic and neuroprotective cleavage product APPs-alpha. The molecular identity of the alpha-secretase has been confirmed recently, and there is consistency about ADAM10 being the most relevant and physiological enzyme of this class. It is not clear to what extent a deficiency in the catalytic activity of ADAM10 contributes to AD pathology and whether a decline occurs in aging humans. Nevertheless, ADAM10 has been suggested as a valuable target for prevention and/or for treatment of Alzheimer's disease. This review focuses on our knowledge about regulation of ADAM10 on different levels of cell physiology, such as transcription and translation, as well as protein-protein interactions and how this especially in the case of transcriptional regulation by retinoic acids might lead to the development of new therapeutic approaches.
淀粉样前体蛋白（APP）通过其β-和γ-分泌酶衍生的裂解产物——A-β肽，在阿尔茨海默病（AD）的发病机制中起关键作用。α-分泌酶提供的另一种加工途径可防止这些毒性肽的形成，并产生神经营养和神经保护的裂解产物 APPs-α。α-分泌酶的分子特性最近已被证实，ADAM10 是此类酶中最相关和最具生理意义的酶。目前尚不清楚 ADAM10 催化活性的缺乏在多大程度上导致 AD 病理，以及在衰老的人类中是否会出现这种情况。然而，ADAM10 已被提议作为预防和/或治疗阿尔茨海默病的有价值的靶点。这篇综述重点介绍了我们对 ADAM10 在细胞生理学不同水平上的调节的了解，例如转录和翻译，以及蛋白-蛋白相互作用，以及这种调节，特别是通过维甲酸的转录调节，如何可能导致新的治疗方法的发展。
