辣椒素对Abeta产生的调控作用及机制研究

Accumulating evidences indicate that capsaicin plays central roles in attenuating oxidative stress and neuroinflammation. Studies also showed that capsaicin had favourable effects on hyperlipidemia, atherosclerosis, hypertension, and so on. Recently, our epidemiological study found that serum Aβ40 level in people with capsaicin-diet was lower than those without capsaicin-diet. Moreover, our preliminary experiment showed that capsaicin down-regulated Aβ and BACE1 levels, up-regulated PPARγ level in neonatal primary cortical neurons from APP/PS1 mice. BACE1 gene promoter possesses some binding sites for transcription factors, including PPARγ. Its activation would suppress the transcription of BACE1 gene. Therefore, we speculate that capsaicin may inhibit the expression of BACE1 through activating PPARγ, thus reducing the generation of Aβ. In this project, different AD neuron model will be applied to study the roles of capsaicin in Aβ generation; SH-SY5Y cells overexpressing APP and BACE1 and hippocampal neurons from BACE1-/- mice will be used to elucidate whether capsaicin regulate Aβ generation via suppressing BACE1 expression; moreover, we intend to explore whether capsaicin inhibit the expression of BACE1 through activating PPARγ via adding PPARγ inhibitor to SH-SY5Y cells overexpressing APP and BACE1; furthermore, we will use APP/PS1/TRPV1-/- mice to explore whether capsaicin active PPARγ through mediating of TRPV1; in addition, we will investigate the preventive and therapeutic effect of capsaicin on AD process using APP/PS1 transgenic mice. The completion of this project will offer novel target for AD therapies via uncovering its underlying pathogenesis.

辣椒素具有抗炎、抗氧化作用。我们前期发现，辣椒素摄入量与认知功能、血液Aβ40水平相关，提示辣椒素可能调控Aβ代谢、干预AD发生。初步研究发现辣椒素降低AD小鼠原代皮层神经元的Aβ及BACE1水平，上调PPARγ。BACE1启动子区有PPARγ结合位点，其激活可抑制BACE1转录。故推测辣椒素可能通过激活PPARγ，抑制BACE1表达，从而减少Aβ产生。本项目拟采用不同AD细胞模型，进一步明确辣椒素对Aβ产生的影响；用过表达APP、BACE1的SH-SY5Y细胞、BACE1-/-小鼠海马神经元，利用PPARγ拮抗剂，探讨辣椒素是否通过激活PPARγ影响BACE1，从而调控Aβ；利用APP/PS1/TRPV1-/-小鼠探讨辣椒素是否由TRPV1介导激活PPARγ；最后采用APP/PS1小鼠，从在体层面探讨辣椒素对AD的防治作用。本项目对于深入阐明AD发病机制、建立AD防治新策略具有重要意义。

背景：阿尔茨海默病（Alzheimer’s disease, AD）是最常见的老年期痴呆类型，目前尚无有效的治疗措施。研究显示中国AD发病率与辣椒饮食的地域分布存在重叠。本研究旨在探讨辣椒的主要辛辣成分辣椒素，是否有治疗AD的潜能。.方法：本研究首先纳入134例非AD患者，以探讨辣椒饮食摄入量与认知和AD脑脊液标志物的相关性。然后利用APP/PS1小鼠和SH-SY5Y细胞，以探讨辣椒素对脑内Aβ负荷的影响及作用机制。.结果：辣椒饮食摄入量与MMSE评分呈正相关，与脑脊液标志物Aβ42呈正相关，与p-tau/Aβ42、t-tau/Aβ42的比率呈负相关，提示辣椒素饮食可能在AD发生中发挥保护性作用。在APP/PS1小鼠中，辣椒素饮食可降低小鼠脑内Aβ负荷并改善认知功能。在体及离体实验显示，辣椒素可通过促进ADAM10的活化，促进APP的α-剪切，从而抑制Aβ产生。同时我们发现，辣椒素可以缓解小鼠脑内的AD样病理，包括tau磷酸化、神经炎症及神经变性。.结论：本研究提示辣椒素具有防治AD的潜能，为未来辣椒或辣椒素作为饮食结构防治AD的临床试验奠定基础。