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

尽管最近的进展，APP家族蛋白在CNS中的生理功能在很大程度上仍然难以捉摸。我们先前产生的APP-KO小鼠被证明是可行的，而APP/APLP 2双敲除（DKO）和三重突变体在出生后不久由于神经肌肉突触传递缺陷而死亡。这表明APP/APLPs在突触形成和功能中的核心作用。为了进一步了解APP/APLP在成年CNS中的功能并避免围产期致死性，我们因此提出产生条件性双敲除小鼠（cDKO）。将最近产生的具有floxed APP（和APLP 2）等位基因的小鼠与CamKII-iCreER小鼠杂交，以在APLP 2缺陷背景下产生前脑特异性和时间点可控的APP-KO（Cre+APPflox/flox APLP 2-/-）。将分析这些小鼠的脑形态、神经元存活、突触形成和功能，以及最终对认知、学习和记忆的功能后果。我们期待着快速的进展，由于合作的表型在财团内的努力。此外，我们打算通过慢病毒介导的Cre递送到APPflox/APPLP 2-/-小鼠的神经原性脑区域中或通过使用NestinCreERT 2 cDKO小鼠选择性地消融神经元干/祖细胞中的APP/APLP表达来研究APP家族脯氨酸对于成体神经发生的作用。从这些研究中，我们期望对APP家族功能的生理学有重大的了解，这对于了解AD的干预策略也至关重要。

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.