Moir Robert D, Tanzi Rudolph E
Genetics and Aging Research Unit, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School - Massachusetts General Hospital, Boston, MA, United States.
Front Aging Neurosci. 2019 Mar 28;11:70. doi: 10.3389/fnagi.2019.00070. eCollection 2019.
The argument is frequently made that the amyloid-β protein (Aβ) persists in the human genome because Alzheimer's disease (AD) primarily afflicts individuals over reproductive age and, therefore, there is low selective pressure for the peptide's elimination or modification. This argument is an important premise for AD amyloidosis models and therapeutic strategies that characterize Aβ as a functionless and intrinsically pathological protein. Here, we review if evolutionary theory and data on the genetics and biology of Aβ are consistent with low selective pressure for the peptide's expression in senescence. Aβ is an ancient neuropeptide expressed across vertebrates. Consistent with unusually high evolutionary selection constraint, the human Aβ sequence is shared by a majority of vertebrate species and has been conserved across at least 400 million years. Unlike humans, the overwhelming majority of vertebrate species do not cease reproduction in senescence and selection pressure is maintained into old age. Hence, low selective pressure in senescence does not explain the persistence of Aβ across the vertebrate genome. The "Grandmother hypothesis" (GMH) is the prevailing model explaining the unusual extended postfertile period of humans. In the GMH, high risk associated with birthing in old age has lead to early cessation of reproduction and a shift to intergenerational care of descendants. The rechanneling of resources to grandchildren by postreproductive individuals increases reproductive success of descendants. In the GMH model, selection pressure does not end following menopause. Thus, evolutionary models and phylogenetic data are not consistent with the absence of reproductive selection pressure for Aβ among aged vertebrates, including humans. Our analysis suggests an alternative evolutionary model for the persistence of Aβ in the vertebrate genome. Aβ has recently been identified as an antimicrobial effector molecule of innate immunity. High conservation across the Chordata phylum is consistent with strong positive selection pressure driving human Aβ's remarkable evolutionary longevity. Ancient origins and widespread conservation suggest the human Aβ sequence is highly optimized for its immune role. We detail our analysis and discuss how the emerging "Antimicrobial Protection Hypothesis" of AD may provide insights into possible evolutionary roles for Aβ in infection, aging, and disease etiology.
人们经常认为，淀粉样β蛋白（Aβ）在人类基因组中持续存在，因为阿尔茨海默病（AD）主要影响生殖年龄以上的个体，因此，该肽的消除或修饰的选择压力较低。这一观点是AD淀粉样变性模型和将Aβ表征为无功能且本质上具有病理性质的蛋白质的治疗策略的重要前提。在此，我们审视进化理论以及关于Aβ的遗传学和生物学数据是否与衰老过程中该肽表达的低选择压力相一致。Aβ是一种在整个脊椎动物中表达的古老神经肽。与异常高的进化选择限制相一致，大多数脊椎动物物种共享人类Aβ序列，并且该序列至少在4亿年中一直保持保守。与人类不同，绝大多数脊椎动物物种在衰老过程中不会停止繁殖，并且选择压力会持续到老年。因此，衰老过程中的低选择压力并不能解释Aβ在整个脊椎动物基因组中的持续存在。“祖母假说”（GMH）是解释人类异常延长的生育后期的主流模型。在GMH中，老年生育相关的高风险导致生殖提前停止，并转向对后代的代际照料。生殖后个体将资源重新导向孙辈会增加后代的生殖成功率。在GMH模型中，选择压力在绝经后并不会结束。因此，进化模型和系统发育数据与包括人类在内的老年脊椎动物中Aβ缺乏生殖选择压力不一致。我们的分析提出了Aβ在脊椎动物基因组中持续存在的另一种进化模型。Aβ最近被确定为先天免疫的抗菌效应分子。整个脊索动物门的高度保守与驱动人类Aβ显著进化长寿的强烈正选择压力相一致。古老的起源和广泛的保守表明人类Aβ序列在其免疫作用方面高度优化。我们详细阐述我们的分析，并讨论新兴的AD“抗菌保护假说”如何为Aβ在感染、衰老和疾病病因学中的可能进化作用提供见解。
