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

阿尔茨海默病是一种缓慢进展的神经退行性疾病，会导致痴呆。主要的病理特征是老年斑、神经原纤维缠结和神经元丢失。老年斑是由淀粉样肽（40-42个氨基酸）组成的，它是由促糖蛋白（APP）产生的。痴呆的病理机制尚不清楚，然而，淀粉样蛋白沉积是最早可能引起其他病理状况的事件之一。因此，现在正在深入研究β -淀粉样蛋白是如何以及在什么细胞间隔中产生的。app首先被β -分泌酶在其细胞外区域切割，然后短段（C99）被γ -分泌酶在其膜内区域切割。有趣的是，由γ -分泌酶切割产生的胞内结构域（现在称为AICD）可能在细胞核中具有转录调节剂的潜在作用。因此，我们计划分析一种新的反式转录调控-分泌酶介导的裂解。然后它的相互作用在溶酶体室中变得不那么明显。我们进一步发现，具有家族性阿尔茨海默病突变的APP与BACE的相互作用更紧密。由FRET检测。此外，这种相互作用对实际的β淀粉样蛋白生成有影响，因为在细胞表面标记后，可以通过ELISA从条件培养基中检测到β淀粉样蛋白。因此，APP和BACE在细胞表面和核内体的相互作用很强，对体外β淀粉样蛋白的生成有实际影响。此外，我们还发现了BACE与APP的内吞受体LRP之间的一种新的相互作用。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。胆固醇消耗实验显示BACE与LRP之间的相互作用减少，这表明LRP可能作为支架连接细胞表面的APP和BACE。在本研究计划中，我们证实了内吞途径是淀粉样蛋白β的产生位点之一，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