大量抑制Aβ产生或促进细胞外Aβ清除药物的临床试验失败表明传统认为阿尔茨海默病（AD）是由于Aβ过度产生或者清除减少，导致Aβ在细胞外以淀粉样斑块或多聚体积累引起神经退行性改变的观点过于简单或并不是关键病理机制。我们前期研究揭示了细胞内Aβ42 积累的潜在新分子机制，而对神经元内Aβ积累所导致的一系列突触前和轴索的结构变化进行时程分析也发现线粒体异常发生最早。说明神经元内，特别是线粒体Aβ积累可引起线粒体出现各种各样的结构功能改变，但其具体机制不清楚。本课题利用表达Aβ42果蝇和APP/PS1小鼠所取得的初步结果和拟将开展的潜在实验结果提示Aβ42以多聚体形式与线粒体加工肽酶（MPP）的beta亚基PMPCB结合，阻碍其与MPP的alpha亚基结合成稳定有效的MMP，导致各种线粒体蛋白的前体加工成熟障碍是Aβ导致线粒体广泛功能结构异常的机制。本研究对开发AD新的治疗靶点奠定理论基础。

The traditional perspective that Alzheimer's disease (AD) is caused by over production or decreased elimination of Abeta causing extracellular Aβ deposition with amyloid plaques leading to neurodegeneration. But this simplified and key pathological mechanism is not supported by the failure of clinical trials through inhibiting Abeta production or promoting extracellular Abeta clearance. Our previous study revealed a potential new molecular mechanism for intraneuronal Aβ42 accumulation. Furthermore, we also indicated a series of presynaptic and axonal structural changes caused by intraneuronal Abeta accumulation and found that mitochondrial abnormality occurred earliest in temporal analysis. Alzheimer’s disease exhibits not only extracellular deposition of amyloid plaques, but also intraneuronal accumulation of Aβ42, especially mitochondrial accumulation of Aβ42, which produces various and distinct structural and functional abnormalities in mitochondria, but the specific mechanism is not clear. This project with preliminary data and the potential results of planned experiments may indicate that Aβ42 binds to the beta unit of mitochondrial processing peptidase--MMP (PMPCB), and blocks its binding to the alpha unit of MMP, thereby impairs the formation of MPP complex resulting inhibiting the processing of various mitochondrial protein precursors and abnormalities. This research work will elucidate the mechanism of Abeta causing extensive dysfunction of mitochondria and establish rationale for developing new therapeutic target of Alzheimer disease.