Analysis of the zinc-dependent functions of the brain-specific protein APLP1

淀粉样前体蛋白(APP)是阿尔茨海默病的重要组成部分，属于包括脑特异蛋白APLP1在内的一个大蛋白家族，其生理功能尚不完全清楚。APP家族蛋白被认为是细胞-表面受体，可能在细胞-细胞和/或细胞-细胞基质相互作用中发挥作用。有证据表明，APP和APLP参与了顺式齐聚，APLP1也通过反式相互作用调节细胞-细胞接触。最近的研究结果表明，APLP1的一种新的锌依赖功能是通过增强生理浓度下APLP1的顺式和反式相互作用来实现的。本项目的目的是在小鼠模型中揭示APLP1的体内功能，特别是这些功能如何依赖于锌的问题。因此，我将在存在或不存在配体的情况下进行活细胞成像研究，并对初级神经元和海马片进行电生理记录。额外的生化分析将补充体内和体外数据。此外，我想研究APLP1基因敲除小鼠在神经元异常方面的表型变化。因此，我将有助于理解APLP1的神经功能，它可能参与突触信号事件，以及APLP1在APP家族中的作用。

The amyloid precursor protein (APP) that is a critical component in Alzheimer’s disease, belongs to a large protein family, including the brain-specific protein APLP1, which physiological functions are not fully understood. The APP family proteins are described as putative cell-surface receptors and may exert functions in cell-cell and/or cell-cellular matrix interactions. This is underlined by evidences that APP and the APLPs are involved in cis oligomerization and that APLP1 also mediates cell-cell contacts by trans interactions. Recent findings suggest a novel zinc-dependent function of APLP1 by enhancing cis and trans interactions of APLP1 at physiological concentrations.The aim of this project is to unravel the in vivo functions of APLP1 in mouse models with a specific focus on the question how these functions depend on zinc. Therefore I will perform live cell imaging studies in the presence or absence of ligands as well as electrophysiological recordings with primary neurons and hippocampal slices. Additional biochemical analysis will complement the in vivo and in vitro data. Further I want to investigate the phenotypical changes of APLP1 knock-out mice in regard to neuronal abnormalities. Thus I will contribute to the understanding of the neuronal functions of APLP1, its possible involvements in synaptic signaling events and the role APLP1 has within the APP family.