The role of the Alzheimer related Amyloid Precursor Protein Gene Family in the Developing and Adult Nervous System

APP是聚集在阿尔茨海默病S病(AD)细胞外斑块中的β-淀粉样多肽的前体蛋白，APP作为APP的前体蛋白在阿尔茨海默病(AD)中的作用是公认的，APP的分泌酶是主要的治疗靶点。相比之下，它的生理功能以及这些功能的丧失是否导致发病机制的问题在很大程度上仍未解决。APP是一个更大的基因家族的成员，包括与APP密切相关的APLP1和APLP2蛋白。为了直接解决APP基因家族的生理功能，我们之前已经产生了围产期死亡的APLP2-/-/APLP1-/-和APLP2-/-/APP-/--小鼠，而APLP1-/-/APP-/-小鼠和单个突变体是存活的。最近，我们培育了三只缺乏APP/APLP家族所有成员的突变小鼠，这些小鼠也在出生后不久死亡。致死性的双突变体没有明显的形态异常，而三个突变体的大脑表现出类似于人类II型无脑的表型，异位成簇的神经母细胞已经通过基底膜和软膜迁移，这表明APP/APLPs在神经元黏附和/或迁移中起作用。总体而言，我们的数据表明APP/APLP对于正常的大脑发育和早期出生后存活是必不可少的。然而，这种围产期的致命性，排除了对出生后和成人衰老神经系统的拟议功能的分析。此外，致命性的潜在机制目前尚不清楚。因此，当前项目的目的是通过两种互补的方法来避免早期死亡。为此，我们打算(A)利用四环素调控的遗传开关(TET-OFF)在出生后下调APP/APLP的表达，从而产生条件零突变体。第二，(B)，我们打算以神经元特异性的方式去除APP的表达，无论是在神经前体细胞发育过程中，还是在出生后有丝分裂后的神经元中。这一方法将揭示致命性是否如假设的那样，是由于神经系统内的功能受损，还是由于周围器官的无关缺陷。我们打算从神经系统的形态和功能成熟，特别是突触发生、神经元可塑性、感觉运动发育以及学习和记忆方面描述这些突变系小鼠的特征。了解APP及其同系物在成人和衰老神经系统中的生理功能，对于揭开导致阿尔茨海默病的失调和致病机制至关重要。

The role of APP as the precursor protein of the ß-amyloid peptide, which accumulates in extracellular plaques in Alzheimer¿s disease (AD), is well established and the secretases processing APP constitute major therapeutic targets. By contrast, its physiological function and the question of whether a loss of these functions contributes to pathogenesis remains largely unresolved. APP is a member of a larger gene family including the closely related APP-like proteins APLP1 and APLP2. To address the physiological functions of the APP gene family directly, we had previously generated APLP2-/-/APLP1-/-- and APLP2-/-/APP-/-- mice that die perinatally, while APLP1-/-/APP-/--mice and single mutants were viable. Recently, we generated triple mutant mice lacking all three APP/APLP family members which also died shortly after birth. Whereas lethal double mutants showed no apparent morphological abnormalities, the brains of triple mutants displayed a phenotype resembling human type II lissencephaly with ectopic clusters of neuroblasts that had migrated through the basal lamina and pial membrane, indicating a role of APP/APLPs in neruonal adhesion and/or migration. Collectively, our data demonstrate that APP/APLPs are essential for normal brain development and early postnatal survival. However, this perinatal lethality, precludes the analysis of proposed functions in the postnatal and adult, aging nervous system. Moreover, the underlying mechanism of lethality is presently unknown. The aim of the current project is thus to circumvent early lethality by two complementary approaches. To this end, we intend to (A) generate conditional null mutants using a tetracycline regulated genetic switch (tet-off) to downregulate APP/APLP expression postnatally. Secondly (B), we intend to ablate APP expression in a neuron-specific manner, either already during development in neural progenitor cells, or in postmitotic neurons postnatally. This approach will unravel whether lethality is, as hypothesized, due to compromised functions within the nervous system or due to unrelated defects in peripheral organs. We intend to characterize these mutant lines of mice with regard to the morphological and functional maturation of the nervous system, in particular synaptogenesis, neuronal plasticity, sensorimotor development, as well as learning and memory. Understanding the physiological functions of APP and its homologous in the adult and aging nervous system will be essential to unravel the misregulation and pathogenic mechanisms that lead to Alzheimer¿s disease.