Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer's Disease.
Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer's Disease.
复制标题
DOI：
10.3389/fnins.2018.00533
复制
发表时间：
2018
影响因子：
4.3
通讯作者：
Lardelli M
中科院分区：
文献类型：
--
作者：
Lumsden AL;Rogers JT;Majd S;Newman M;Sutherland GT;Verdile G;Lardelli M
导致早发性家族性阿尔茨海默病（EOfAD）的绝大多数显性突变仅发生在PSEN 1、PSEN 2和APP三个基因中。这些突变的共同效应是APP衍生肽-淀粉样蛋白β（Aβ）的产生改变。正是这一关键事实奠定了淀粉样蛋白假说的权威性，该假说已经为阿尔茨海默病研究提供了二十多年的信息。任何挑战这一权威必须提供一个替代的解释PSEN基因和APP之间的关系。在本文中，我们探讨了一种可能的替代关系-细胞铁稳态失调作为一个共同的影响EOfAD突变在这些基因。这个想法是有吸引力的，因为它提供了EOfAD突变和阿尔茨海默病的主要特征之间的明确联系，如线粒体功能障碍，血管风险因素/缺氧，能量代谢和炎症。我们将我们的想法与其他人的观察相结合，描述了阿尔茨海默病的“压力阈值状态变化”模型，该模型可能开始解释EOfAD和迟发性散发（LOsAD）形式的疾病的存在。指导研究调查铁稳态失调在EOfAD中的作用可能是我们努力了解这种形式的痴呆症的一个有益的方法。
The overwhelming majority of dominant mutations causing early onset familial Alzheimer’s disease (EOfAD) occur in only three genes, PSEN1, PSEN2, and APP. An effect-in-common of these mutations is alteration of production of the APP-derived peptide, amyloid β (Aβ). It is this key fact that underlies the authority of the Amyloid Hypothesis that has informed Alzheimer’s disease research for over two decades. Any challenge to this authority must offer an alternative explanation for the relationship between the PSEN genes and APP. In this paper, we explore one possible alternative relationship – the dysregulation of cellular iron homeostasis as a common effect of EOfAD mutations in these genes. This idea is attractive since it provides clear connections between EOfAD mutations and major characteristics of Alzheimer’s disease such as dysfunctional mitochondria, vascular risk factors/hypoxia, energy metabolism, and inflammation. We combine our ideas with observations by others to describe a “Stress Threshold Change of State” model of Alzheimer’s disease that may begin to explain the existence of both EOfAD and late onset sporadic (LOsAD) forms of the disease. Directing research to investigate the role of dysregulation of iron homeostasis in EOfAD may be a profitable way forward in our struggle to understand this form of dementia.
登录
查看更多内容
影响因子：
11.4
作者：
Area-Gomez, Estela;Castillo, Maria Del Carmen Lara;Tambini, Marc D.;Guardia-Laguarta, Cristina;de Groof, Ad J. C.;Madra, Moneek;Ikenouchi, Junichi;Umeda, Masato;Bird, Thomas D.;Sturley, Stephen L.;Schon, Eric A.
通讯作者：
Schon, Eric A.
影响因子：
7.4
作者：
Baksi S;Tripathi AK;Singh N
通讯作者：
Singh N
影响因子：
9
作者：
Area-Gomez E;de Groof A;Bonilla E;Montesinos J;Tanji K;Boldogh I;Pon L;Schon EA
通讯作者：
Schon EA
影响因子：
4.2
作者：
Bamne MN;Demirci FY;Berman S;Snitz BE;Rosenthal SL;Wang X;Lopez OL;Kamboh MI
通讯作者：
Kamboh MI
影响因子：
20.1
作者：
Bishop T;Ratcliffe PJ
通讯作者：
Ratcliffe PJ