Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute (DFCI), Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, 02115, USA.
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Sci Rep. 2022 Jan 7;12(1):66. doi: 10.1038/s41598-021-04027-8.
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 α- or β- and γ-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.
淀粉样前体蛋白（APP）与家族性和散发性阿尔茨海默病均相关。APP 有两个同源物，即淀粉样前体样蛋白 1 和 2（APLP1 和 APLP2），它们具有功能冗余性。APP 细胞内 C 端结构域（AICD）通过顺序 α 或 β 和 γ 分泌酶切割产生，被认为可以控制基因表达，类似于 Notch 的 ICD。为了研究 APP 家族在转录调控中的作用，我们检查了 APP/APLP1/APLP2 条件性三敲除（cTKO）小鼠大脑皮层中的基因表达变化，在该模型中 APP 家族成员在出生后前脑的兴奋性神经元中被选择性失活。在 12 个先前报道的 AICD 靶基因中，只有 Nep 和 Npas4 的 mRNA 水平在 cTKO 小鼠的大脑皮层中与同窝对照相比显著降低。我们通过 RNA-seq 进一步检查了全局转录变化，发现 cTKO 小鼠的新皮层和海马体中分别有 189 个和 274 个差异表达基因，与对照组相比。GO 分析表明，这些基因参与多种细胞功能，包括细胞外组织、学习和记忆以及离子通道。因此，APP 家族的失活改变了大脑皮层的转录谱，并影响了广泛的分子途径。
