Dissecting the two different modes of Amyloid precursor protein (APP) function: as soluble ligand and/or as synaptic adhesion molecule

除了在阿尔茨海默病发病机制中的基础作用外，淀粉样前体蛋白(APP)在突触具有重要的生理功能，我们可以在之前对缺乏APP的基因敲除(KO)小鼠的研究中表明。有趣的是，大多数APP-KO赤字只是随着年龄的增长而出现的。然而，当APP-KO小鼠与缺乏APP同源APLP2的小鼠杂交时，这会导致早期出生后死亡，这表明功能重叠。APP/APLP2缺陷小鼠的缺陷包括外周和中枢突触损伤，包括神经肌肉接头畸形、中枢神经系统脊椎密度降低、LTP缺陷以及学习和记忆障碍。值得注意的是，APP功能的潜在分子机制尚不清楚。APP介导的黏附功能与APP胞外分泌之间的关系是目前尚未解决的关键问题之一。一方面，我们和其他人可以证明主要的APP处理产品之一APPS-α对神经元的生存和功能至关重要，因为它具有神经营养、神经保护、神经生成和突触生成功能，以及神经元的可塑性和增强记忆的特性。另一方面，我们可以提供令人信服的证据，证明全长表面定位的APP-FL可能作为一种突触细胞黏附分子发挥功能，类似于神经连接蛋白和神经瑞新。这一假说目前主要由体外数据支持，目前尚不清楚APP在三叉神经节和中枢神经系统中的具体功能分别依赖于内源性APP-α分泌或APP-FL介导的黏附。最近，我们在体外分析了不同的APP突变体，这些突变体要么缺乏APP-α分泌，要么不反式二聚体。使用这些APP突变体，我们可以清楚地区分APP和APP-FL功能，现在评估它们在体内的特性将是至关重要的。为此，我们将产生新的APP敲击小鼠，这些小鼠要么缺乏APPS胞外域的分泌，要么缺乏跨突触黏附。我们将详细研究PNS和CNS在神经元和突触形态、突触功能和可塑性以及行为方面的后果。总的来说，这些研究将使我们能够破译哪些应用程序的功能主要依赖于APP-FL或秘密应用程序。我们的结果将对更好地理解需要突触稳定的过程之间的相互作用，如突触发生和突触维持，或者相反，需要通过蛋白水解性切割黏附分子进行突触重塑的过程之间的相互作用。此外，我们的研究对于评估以APP处理或APP-FL水平为目标的药物疗法的风险至关重要，因此可能会干扰APP的生理功能。

In addition to its fundamental role in the pathogenesis of Alzheimer’s disease, the amyloid precursor protein (APP) has essential physiological functions at the synapse, as we could show in previous studies of knockout (KO) mice lacking APP. Interestingly, most of the APP-KO deficits emerge only with aging. However, when APP-KO mice are bred with mice lacking the APP homologue APLP2, this results in early postnatal death, suggesting overlapping functions. Deficits of APP/APLP2 deficient mice encompass peripheral and central synaptic impairments, including malformation of the neuromuscular junction, reduced spine density in the CNS, LTP deficits and impairments in learning and memory. Notably, the underlying molecular mechanism of APP function is yet unclear. One of the still unresolved key questions is the relationship between APP mediated adhesive functions and APP ectodomain secretion. At one hand, we and others could show that one of the major APP processing products, APPs-alpha, is pivotal for neuronal viability and function, as it has neurotrophic, neuroprotective, neurogenic and synaptogenic functions, as well as neuronal plasticity and memory enhancing properties. On the other hand, we could provide compelling evidence that full-length surface localized APP-FL may function as a synaptic cell adhesion molecule, similar to Neuroligin and Neurexin. This latter hypothesis is yet mainly supported by in vitro data and it is currently unclear, which specific in vivo functions of APP in the PNS and CNS are dependent on endogenous APPs-alpha secretion or APP-FL mediated adhesion, respectively. Recently, we analyzed different APP mutants in vitro, that are either deficient in APPs-alpha secretion or that do not trans-dimerize. Using these APP mutants we could clearly differentiate between APPs and APP-FL functions and it will now be crucial to assess their properties in vivo. To this end we will generate novel APP knockin mice deficient either in the secretion of the APPs ectodomain or deficient in trans-synaptic adhesion. We will study in detail the consequences for PNS and CNS physiology with regard to neuronal and synaptic morphology, synaptic function and plasticity, as well as behavior. Collectively, these studies will allow us to decipher which APP functions depend primarily on APP-FL or secreted APPs. Our results will have implications for better understanding the interplay between processes that require synaptic stabilization such as synaptogenesis and synapse maintenance or, conversely, processes that require synaptic remodeling by proteolytic cleavage of adhesion molecules. In addition, our studies will be crucial to estimate the risk of pharmacotherapies that target APP processing or APP-FL levels and may thus interfere with physiological APP functions.