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

点击翻译按钮获取中文摘要

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.