The role of the amyloid precursor protein gene family in the adult mouse CNS

尽管最近取得了进展，但APP家族蛋白在中枢神经系统中的生理功能(S)在很大程度上仍然难以捉摸。我们之前培育的APP-KO小鼠被证明是可行的，而APP/APLP2双基因敲除(DKO)和三重突变在出生后不久就由于神经肌肉突触传递缺陷而死亡。这表明APP/APLP在突触的形成和功能中起着核心作用。为了进一步了解APP/APLP在成年中枢神经系统中的功能，并避免围产期死亡，我们建议建立条件性双基因敲除小鼠(CDKO)。新生的APP(和APLP2)等位基因小鼠将与CaMKII-iCreer小鼠杂交，在APLP2缺失的背景下产生前脑特异的、时间点可控的APP-KO(CRE+APPflx/Flox APLP2-/-)。这些小鼠将被分析关于大脑形态、神经元存活、突触形成和功能，最后是对认知、学习和记忆的功能后果。我们预计，由于财团内部的合作表型工作，该项目将取得快速进展。此外，我们打算研究APP家族蛋白在成年神经发生中的作用，无论是通过慢病毒介导的CRE传递到APPflx/FloxAPLP2-/-小鼠的神经源性脑区，还是通过使用NestinCreERT2 cDKO小鼠选择性地阻断神经干细胞/祖细胞中APP/APLP的表达。从这些研究中，我们期待对APP家族功能的生理学有更深入的了解，这对于了解AD的干预策略也是至关重要的。

Despite recent progress the physiological fimction(s) of APP family proteins in the CNS has remained largely elusive. We previously generated APP-KO mice that proved viable whereas APP/APLP2 double knockouts (DKO) and triple mutants died shortly after birth due to defects in neuromuscular synaptic transmission. This suggests a central role for APP/APLPs in synapse formation and function. To gain further insights into APP/APLP functions in the adult CNS and to circumvent perinatal lethality we therefore propose to generate condifional double knockout mice (cDKO). Recenfiy generated mice with floxed APP (and APLP2) alleles will be crossed with CamKII-iCreER mice to generate a forebrain-specific and time point controllable APP-KO on an APLP2-deficient background (Cre+APPflox/flox APLP2-/-). These mice will be analyzed with regard to brain morphology, neuronal survival, synapse formation and funclion, and finally functional consequences for cognition, learning and memory. We expect a rapid progress due to the collaborative phenotyping effort within the consortium. In addition, we intend lo study the role of APP family proleins for adult neurogenesis either via lentivims-mediated Cre delivery into neurogenic brain areas of APPflox/floxAPLP2-/- mice or by ablafing APP/APLP expression selectively in neuronal stem/progenitor cells using NestinCreERT2 cDKO mice. From these studies we expect major insights into the physiology of APP family functions that is also crucial to know for strategies of intervention in AD.