γ-分泌酶亚基presenilin(PS)，presenilin enhancer2 (Pen2)和nicastrin(NCT)与家族性阿尔茨海默氏病的发生有密切联系。PS具有依赖于γ-分泌酶和独立于γ-分泌酶的功能，但它以哪一种方式参与突触可塑性和成年神经元存活的过程还有很大争议。Pen2和NCT对全长PS的表达有截然相反的作用。Pen2在成年大脑中正常的生理功能还未有报道。我们前期工作表明NCT对认知功能有重要作用，但还不清楚它对突触可塑性的贡献。我们的假说是Pen2依赖的γ-分泌酶活性在突触可塑性，认知功能和神经元存活中有重要作用。我们将采用Cre-loxP技术使Pen2在前脑神经元中条件性地失活以研究它的正常生理功能。我们还将比较Pen2和NCT调控细胞凋亡的分子机制是否有差异。这些研究可阐明Pen2调控成年神经元存活和认知功能的机制，也有助发现新的治疗靶点以预防神经退行死亡。

Presenilin (PS)，presenilin enhancer2 (Pen2) and nicastrin (NCT) are key subunits of the γ-secretase complex, and are associated with familial Alzheimer's disease (AD). PS possesses both γ-secretase-dependent and -independent functions. Accumulating evidence has indicated that presenilins (PSs) are required for synaptic plasticity, memory and neuronal survival. However, it is unclear whether PSs carry out these essential functions through a γ-secretase-dependent or -independent manner. In vitro evidence has shown that expression levels of full-length PS are down-regulated by loss of NCT, but are up-regulated by loss of Pen2. Our recent study has revealed essential roles of NCT in cognitive function and neuronal survival. However, it remains completely unknown whether Pen2 is important for synaptic plasticity, memory and neuronal survival. Our central hypothesis is that Pen2 plays essential roles in these physiological processes. To test it, we will take advantage of Cre-LoxP recombination technology to inactivate Pen2 specifically in forebrain excitatory neurons of the mice, which allows us to study its normal physiological functions. We will also study molecular mechanisms by which NCT and Pen2 regulate apoptosis in adult brains through direct comparisons of the two different lines of forebrain-specific NCT and Pen2 conditional knockout mice. Elucidation of novel roles of Pen2 will provide significant insights on molecular mechanisms for cognitive impairment and cell death in neurodegenerative diseases, and may further help identify novel therapeutic targets for the treatment or prevention of neurodegeneration.