Regulation of gene expression by the APP family in the adult cerebral cortex

Amyloid precursor protein (APP) is associated with both familial and sporadic forms of Alzheimer's disease. APP has two homologs, amyloid precursor-like protein 1 and 2 (APLP1 and APLP2), and they have functional redundancy. APP intracellular c-terminal domain (AICD), produced by sequential alpha- or beta- and gamma-secretase cleavages, is thought to control gene expression, similarly as the ICD of Notch. To investigate the role of APP family in transcriptional regulation, we examined gene expression changes in the cerebral cortex of APP/APLP1/APLP2 conditional triple knockout (cTKO) mice, in which APP family members are selectively inactivated in excitatory neurons of the postnatal forebrain. Of the 12 previously reported AICD target genes, only Nep and Npas4 mRNA levels were significantly reduced in the cerebral cortex of cTKO mice, compared to littermate controls. We further examined global transcriptional changes by RNA-seq and identified 189 and 274 differentially expressed genes in the neocortex and hippocampus, respectively, of cTKO mice relative to controls. Gene Ontology analysis indicated that these genes are involved in a variety of cellular functions, including extracellular organization, learning and memory, and ion channels. Thus, inactivation of APP family alters transcriptional profiles of the cerebral cortex and affects wide-ranging molecular pathways. mRNA expression profiles of control and APP/APLP1/APLP2 triple conditional knockout (cTKO) in the neocortex and hippocampus淀粉样前体蛋白（Amyloid precursor protein, APP）与家族性和散发性阿尔茨海默病均存在关联。APP拥有两个同源物，即淀粉样前体蛋白样蛋白1和2（APLP1与APLP2），二者具备功能冗余性。经依次α-、β-及γ-分泌酶切割产生的APP细胞内C端结构域（APP intracellular c-terminal domain, AICD），被认为可调控基因表达，其功能与Notch的细胞内结构域（ICD）相仿。为探究APP家族在转录调控中的作用，我们对APP/APLP1/APLP2条件性三重敲除（conditional triple knockout, cTKO）小鼠的大脑皮层基因表达变化进行了检测——该模型中APP家族成员在出生后脑前区的兴奋性神经元内被选择性失活。相较于同窝对照小鼠，在12个此前已报道的AICD靶基因中，仅Nep和Npas4的mRNA水平在cTKO小鼠大脑皮层中显著下调。我们进一步通过RNA测序（RNA-seq）分析了全局转录变化，结果显示相较于对照组，cTKO小鼠的新皮层与海马体中分别存在189个和274个差异表达基因。基因本体论（Gene Ontology）分析表明，这些基因参与了多种细胞生物学过程，包括细胞外组织构建、学习与记忆以及离子通道相关功能。综上，APP家族的失活会改变大脑皮层的转录谱，并影响广泛的分子通路。对照与APP/APLP1/APLP2条件性三重敲除（cTKO）小鼠新皮层及海马体的mRNA表达谱