Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI, USA.
J Alzheimers Dis. 2023;92(1):29-57. doi: 10.3233/JAD-221042.
Amyloid-β protein precursor (AβPP) gives rise to amyloid-β (Aβ), a peptide at the center of Alzheimer's disease (AD). AβPP, however, is also an ancient molecule dating back in evolution to some of the earliest forms of metazoans. This suggests a possible ancestral function that may have been obscured by those that evolve later. Based on literature from the functions of Aβ/AβPP in nervous system development, plasticity, and disease, to those of anti-microbial peptides (AMPs) in bacterial competition as well as mechanisms of cell competition uncovered first by Drosophila genetics, I propose that Aβ/AβPP may be part of an ancient mechanism employed in cell competition, which is subsequently co-opted during evolution for the regulation of activity-dependent neural circuit development and plasticity. This hypothesis is supported by foremost the high similarities of Aβ to AMPs, both of which possess unique, opposite (i.e., trophic versus toxic) activities as monomers and oligomers. A large body of data further suggests that the different Aβ oligomeric isoforms may serve as the protective and punishment signals long predicted to mediate activity-dependent axonal/synaptic competition in the developing nervous system and that the imbalance in their opposite regulation of innate immune and glial cells in the brain may ultimately underpin AD pathogenesis. This hypothesis can not only explain the diverse roles observed of Aβ and AβPP family molecules, but also provide a conceptual framework that can unify current hypotheses on AD. Furthermore, it may explain major clinical observations not accounted for and identify approaches for overcoming shortfalls in AD animal modeling.
淀粉样蛋白-β 前体（AβPP）产生淀粉样蛋白-β（Aβ），该肽是阿尔茨海默病（AD）的核心。然而，AβPP 也是一种古老的分子，在进化过程中可以追溯到一些最早的后生动物形式。这表明可能存在一种原始功能，而后来进化出的功能可能会掩盖这种原始功能。基于 Aβ/AβPP 在神经系统发育、可塑性和疾病中的作用的文献，以及抗菌肽（AMPs）在细菌竞争中的作用，以及首先由果蝇遗传学揭示的细胞竞争机制，我提出 Aβ/AβPP 可能是细胞竞争中古老机制的一部分，随后在进化过程中被用于调节活性依赖的神经回路发育和可塑性。这一假说得到了以下几个方面的支持：首先，Aβ 与 AMPs 非常相似，两者都具有独特的、相反的（即营养性与毒性）活性，无论是单体还是低聚物。大量数据进一步表明，不同的 Aβ 寡聚体亚型可能作为活性依赖的轴突/突触竞争的保护和惩罚信号，长期以来一直预测这些信号可以调节发育中的神经系统中的活性依赖的轴突/突触竞争，而其对固有免疫和大脑中神经胶质细胞的相反调节的失衡可能最终是 AD 发病机制的基础。这一假说不仅可以解释 Aβ 和 AβPP 家族分子观察到的多种作用，还可以提供一个概念框架，可以统一目前关于 AD 的假说。此外，它可能解释了尚未解释的主要临床观察结果，并确定了克服 AD 动物模型不足的方法。
