A novel transcriptional regulation mechanism regulated by Alzheimer-related proteins.

阿尔茨海默病是一种缓慢进行的神经退行性疾病，导致痴呆。主要病理特征为老年斑、神经元缠结和神经元丢失。老年斑是由前体蛋白（procursor protein，APP）产生的40-42个氨基酸的β-淀粉样肽（amyloid-beta peptides，AP）组成的，其发病机制目前还不清楚，但β-淀粉样肽的沉积是引起痴呆的最早期事件之一。因此，目前正在深入研究淀粉样β蛋白是如何以及在什么样的细胞隔室中产生的。APP首先在其胞外结构域被β-分泌酶切割，然后在其膜内结构域被γ-分泌酶切割。有趣的是，由γ-分泌酶切割产生的细胞内结构域（现在称为AICD）可能在细胞核中具有作为转录调节剂的潜在作用。因此，我们计划分析一个新的跨 关于我们 γ-分泌酶介导的裂解调节，然后其相互作用变得不那么宏伟的溶酶体区室。我们进一步发现，有家族性阿尔茨海默病突变的APP与BACE有更紧密的相互作用。此外，这种相互作用对实际的淀粉样蛋白-β产生有影响，因为在细胞表面标记后通过ELISA从条件培养基中检测到淀粉样蛋白-β。因此，APP和BACE之间的相互作用在细胞表面和内体中很强，这对体外淀粉样蛋白-β产生有实际影响。此外，我们检测到BACE和LRP之间的新相互作用，有趣的是，LRP似乎与细胞表面的BACE相互作用，特别是在脂筏中，BACE应该遇到APP。胆固醇耗竭实验显示BACE与LRP之间的相互作用减弱，这表明LRP可能作为细胞表面连接APP和BACE的支架。我们证实了内吞途径是淀粉样β蛋白产生的位点之一，LRP可能作为连接它们的支架。少

Alzheimer's disease is a slowly progressive neurodegenerative disorder which causes dementia. The mail pathological hallmarks are senile plaques, neurofibrillary tangles and neuronal loss. The senile plaques are made of amyloid-beta peptides (40-42 amino acids), which are generated from the procursor protein (APP).The pathological mechanism which underlies the dementia is not exactly known yet, however, the deposition of amyloid-beta is one of the earliest event which may cause other pathological conditions. Therefore, it is now under intensive investigation how and in what cellular compartment amyloid-beta is generatedAPP is first cleaved by beta-secretase at its extracellular domain, then the stub (C99) is cleaved by gamma-secretase at its intramembrane domain. Interestingly, the intracellular domain (which is now called AICD) generated by gamma-secretase cleavage, may have a potential role as a transcriptional modulator, in the nucleus. Therefore, we planned to analyze a novel trans … More criptional regulation by gamma-secretase-mediated cleavage.Then its interaction became less magnificent in lysosomal compartment. We further found that APP with mutation of familial Alzheimer's disease had tighter interaction with BACE. detected by FRET.Further, this interaction had an impact on actual amyloid-beta generation, since amyloid-beta was detected from the conditioned media by ELISA after the cell surface labeling.Therefore, the interaction between APP and BACE is strong on the cell surface and in the endosomes, which has actual impact on amyloid-beta generation in vitro.Furthermore, we detected a novel interaction between BACE and LRP, an endocytic receptor for APP. Interestingly, LRP seems to interact with BACE on the cell surface, especially in the lipid rafts, where, BACE is supposed to encounter APP. The cholesterol depletion experiments showed a decrease of the interaction between BACE and LRP, suggesting that LRP may play as a scaffold to connect APP and BACE on the cell surface.In this research plan, we confirmed that an endocytic pathway is one of the amyloid-beta generation sites and LRP may play as a scaffold to connect them. Less