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

淀粉样蛋白前体蛋白（APP）除了在阿尔茨海默病发病机制中发挥基本作用外，在突触中也具有必要的生理功能，正如我们在先前对缺乏APP的敲除（KO）小鼠的研究中所显示的那样。有趣的是，大多数APP-KO缺陷仅随着年龄的增长而出现。然而，当APP- ko小鼠与缺乏APP同源物APLP2的小鼠杂交时，会导致出生后早期死亡，提示功能重叠。APP/APLP2缺陷小鼠的缺陷包括外周和中枢突触损伤，包括神经肌肉连接处畸形、中枢神经系统脊柱密度降低、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外结构域分泌之间的关系是尚未解决的关键问题之一。一方面，我们和其他人可以证明APP的主要加工产物之一APP -alpha对神经元的活力和功能至关重要，因为它具有神经营养、神经保护、神经发生和突触发生功能，以及神经元可塑性和记忆增强特性。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可能作为突触细胞粘附分子，类似于Neuroligin和Neurexin。后一种假设主要得到体外实验数据的支持，目前尚不清楚APP在PNS和CNS中的具体体内功能分别依赖于内源性APP- α分泌或APP- fl介导的粘附。最近，我们在体外分析了不同的APP突变体，它们要么缺乏APP - α分泌，要么不进行反式二聚体化。利用这些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敲入小鼠，这些小鼠要么缺乏APP外域的分泌，要么缺乏跨突触粘附。我们将详细研究PNS和CNS生理学在神经元和突触形态、突触功能和可塑性以及行为方面的影响。总的来说，这些研究将使我们能够破译哪些APP功能主要依赖于APP- fl或分泌的APP。我们的研究结果将有助于更好地理解需要突触稳定（如突触发生和突触维持）的过程之间的相互作用，或者相反，需要通过黏附分子的蛋白水解裂解来重塑突触的过程。此外，我们的研究对于评估针对APP加工或APP- fl水平的药物治疗的风险至关重要，这些药物治疗可能会干扰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.