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

淀粉样前体蛋白（APP）是阿尔茨海默病的关键成分，属于一个大的蛋白质家族，包括脑特异性蛋白APLP 1，其生理功能尚未完全了解。APP家族蛋白被描述为推定的细胞表面受体，并且可以在细胞-细胞和/或细胞-细胞基质相互作用中发挥功能。APP和APLPs参与顺式寡聚化，APLP 1也通过反式相互作用介导细胞-细胞接触的证据强调了这一点。最近的研究结果表明，锌依赖的APLP 1的一个新的功能，通过增强顺式和反式相互作用的APLP 1在生理浓度。本项目的目的是解开在小鼠模型中的APLP 1的体内功能，特别是这些功能如何依赖于锌的问题。因此，我将在配体存在或不存在的情况下进行活细胞成像研究，以及对原代神经元和海马切片进行电生理记录。其他生化分析将补充体内和体外数据。此外，我想研究APLP 1基因敲除小鼠在神经元异常方面的表型变化。因此，我将有助于了解APLP 1的神经元功能，其可能参与突触信号事件和APLP 1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.