Lehrer Steven, Rheinstein Peter H
Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Severn Health Solutions, Severna Park, MD 21146, USA.
World Acad Sci J. 2020 Nov-Dec;2(6). doi: 10.3892/wasj.2020.68. Epub 2020 Sep 22.
The cause of Alzheimer's disease (AD) is poorly understood. In 1991, the amyloid hypothesis postulated that β-amyloid (Aβ) accumulation is a key element. It follows that clearing the brain of Aβ would be beneficial, which has not been the case. Therefore, Aβ is likely a result, not a cause, of AD and may be protective rather than harmful. The apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for AD. Klotho (KL), encoded by the KL gene, may be another AD-related protein. FGF21 is a circulating endocrine hormone, mainly secreted by the liver, mostly during fasting. FGF21 acts by binding to its receptor FGFR1 and co-receptor β-klotho. FGF21 is neuroprotective and could delay onset of AD. In the present study, the KL protein structure was examined to determine whether it may interact with Aβ. Protein data bank (pdb) entries for klotho and Aβ were searched on the RCSB Protein Data Bank for β-KL and AD amyloid β-peptide. The protein structures were superimposed and aligned on PYMOL v2.3.4 with the super command, which super aligns two protein selections. To evaluate the conservation and alignment of the Aβ and KL genomes across species, BLAT, the Blast-Like Alignment Tool of the UCSC Genome Browser, was used. The amino acid residues phe76-val96 of KL aligned closely with residues asp7-asn27 of Aβ. Cross-species comparison of KL revealed a high degree of alignment and conservation in the chimp and 27 other primates; however, less alignment and conservation were observed in the mouse, dog and elephant, even less in the chicken, western clawed frog (), zebrafish and lamprey. The current finding of amino acid residues phe76-val96 of klotho aligning closely with residues asp7-asn27 of Aβ suggests that Aβ can enhance the ability of klotho to draw FGF21 to regions of incipient neurodegeneration in AD. The problem arises with age. Older individuals do not heal or repair tissue damage as well as younger individuals. As neurodegeneration advances in an older individual, perhaps caused by neuroinflammation related to herpes simplex virus type 1, increasing amounts of amyloid are produced, forming an adhesive web, as the brain tries to hold the pathologic process in check. Meanwhile, the damage increases and spreads. Progressive neurodegeneration and cognitive decline are the outcome.
阿尔茨海默病（AD）的病因尚不清楚。1991年，淀粉样蛋白假说提出β-淀粉样蛋白（Aβ）的积累是一个关键因素。由此推断，清除大脑中的Aβ会有益处，但实际并非如此。因此，Aβ可能是AD的结果而非病因，并且可能具有保护作用而非有害作用。载脂蛋白E4（apoE4）等位基因是AD最强的遗传风险因素。由KL基因编码的klotho（KL）可能是另一种与AD相关的蛋白质。成纤维细胞生长因子21（FGF21）是一种循环内分泌激素，主要由肝脏分泌，大多在禁食期间分泌。FGF21通过与其受体FGFR1和共受体β-klotho结合发挥作用。FGF21具有神经保护作用，可延缓AD的发病。在本研究中，对KL蛋白结构进行了检测，以确定它是否可能与Aβ相互作用。在RCSB蛋白质数据库中搜索β-KL和AD淀粉样β肽的klotho和Aβ的蛋白质数据库（pdb）条目。利用PYMOL v2.3.4中的super命令将蛋白质结构进行叠加和比对，该命令可对两个蛋白质选择进行超级比对。为了评估跨物种Aβ和KL基因组的保守性和比对情况，使用了加州大学圣克鲁兹分校基因组浏览器的类Blast比对工具BLAT。KL的第76位苯丙氨酸至第96位缬氨酸的氨基酸残基与Aβ的第7位天冬氨酸至第27位天冬酰胺的残基紧密比对。KL的跨物种比较显示，在黑猩猩和其他27种灵长类动物中具有高度的比对和保守性；然而，在小鼠、狗和大象中观察到的比对和保守性较低，在鸡、西部爪蟾、斑马鱼和七鳃鳗中更低。目前发现klotho的第76位苯丙氨酸至第96位缬氨酸的氨基酸残基与Aβ的第7位天冬氨酸至第27位天冬酰胺的残基紧密比对，这表明Aβ可以增强klotho将FGF21吸引到AD早期神经退行性变区域的能力。问题随着年龄的增长而出现。老年人修复组织损伤的能力不如年轻人。随着老年人神经退行性变的进展，可能是由与1型单纯疱疹病毒相关的神经炎症引起的，淀粉样蛋白的产生量增加，形成一个黏附网络，因为大脑试图控制病理过程。与此同时，损伤不断增加并扩散。渐进性神经退行性变和认知衰退就是结果。
