Thome J, Kornhuber J, Münch G, Schinzel R, Taneli Y, Zielke B, Rösler M, Riederer P
Psychiatrische Klinik und Poliklinik, Universitäts-Nervenklinik, Würzburg.
Nervenarzt. 1996 Nov;67(11):924-9. doi: 10.1007/s001150050073.
Despite intense efforts, it has not yet been possible to clarify the etiopathogenesis of Alzheimer's dementia. There are, however, hypotheses which focus on certain aspects of this type of dementia, characterized by particular neuropathological alterations and clinical correlates. Recently, evidence has accumulated that advanced glycation endproducts (AGEs) could play an important role in the etiology of the Alzheimer's syndrome. AGEs are generated by an irreversible reaction through the non-enzymatic, long-term glycosylation of proteins. They are strongly resistant to proteolytic processes and induce protein crosslinking. They could thus inhibit the physiological functions of many proteins. Moreover, it is suggested that they contribute to the transformation of the soluble form of beta-amyloid into its unsoluble version. AGEs are also demonstrable in neurofibrillary tangles (NFTs). A further mechanism by which AGEs might be pathogenic is via their induction of oxidative stress. AGEs probably exert their pathological effects not only directly because of their chemical properties, but also by indirect receptor-mediated mechanisms. Further investigation of AGE-mediated mechanisms should reveal their role in the etiopathogenesis of the Alzheimer's syndrome and, finally, lead to the development of new pharmacological strategies aimed at inhibiting protein cross-linking.
尽管付出了巨大努力，但仍未能阐明阿尔茨海默病性痴呆的病因发病机制。然而，有一些假说聚焦于这类痴呆的某些方面，其特征为特定的神经病理学改变和临床相关表现。最近，越来越多的证据表明晚期糖基化终末产物（AGEs）可能在阿尔茨海默综合征的病因中起重要作用。AGEs是通过蛋白质的非酶促长期糖基化的不可逆反应产生的。它们对蛋白水解过程具有很强的抗性，并诱导蛋白质交联。因此，它们可能会抑制许多蛋白质的生理功能。此外，有人认为它们有助于β-淀粉样蛋白的可溶性形式转化为不溶性形式。在神经原纤维缠结（NFTs）中也可检测到AGEs。AGEs可能致病的另一种机制是通过诱导氧化应激。AGEs可能不仅因其化学性质直接发挥病理作用，还通过间接的受体介导机制发挥作用。对AGE介导机制的进一步研究应能揭示它们在阿尔茨海默综合征病因发病机制中的作用，并最终导致旨在抑制蛋白质交联的新药理学策略的开发。
