国内外研究和我们前期结果均显示神经元内apoE4(1-272)是致阿尔茨海默病(AD)病变的主要apoE4分子，但机制尚不清。我们前期研究发现神经元内apoE4(1-272)可诱发内质网应激(ERS)和线粒体形态功能紊乱，同时伴有线粒体分裂、融合蛋白表达和修饰异常；且线粒体形态功能紊乱发生在ERS之后；采用ERS保护剂4-PBA干预后可显著改善线粒体形态功能。因此提出神经元内apoE4(1-272)可能通过诱发ERS，损害线粒体融合分裂动态，促使线粒体出现形态及功能紊乱，导致神经细胞变性。本项目拟利用前期建立的apoE4(1-272)转基因鼠和四环素可调控的apoE4(1-272)表达细胞模型，深入探讨神经元内apoE4(1-272)致线粒体形态功能紊乱的可能分子机制，验证ERS是apoE4(1-272)致线粒体动态失衡的关键环节，为apoE4致AD发病的机制提供新的科学依据。

It is well known that apoE4 hydrolysis fragments (1-272) is the key molecular marker of neurodegeneration in Alzheimer's disease (AD), which can lead to neurotoxicities in neurons，but the molecular mechanism is not clear. Our previous results showed that apoE4 (1-272) fragments could induce endoplasmic reticulum stress(ER Sress) and mitochondrial dysfunction while the abnormal expression and modification of mitochondria fusion and fission proteins were detected in neurons. ER stress was also found before occuring mitochondrial dysfunction. Thus, apoE4(1-272) fragments through triggering ER stress -induced mitochondrial fragmentation may promote the damage of mitochondrial function, lead to neurodegeneration.By using of the pre-established neuron-specific apoE4 (1-272) expression transgenic mice , tetracycline controlling apoE4 (1-272) expression cell model and the multiple research tools such as ultrastructural pathology, morphology, biology, physics, biochemistry, molecular biology technology, we will verify the above assumptions. Our results will for the first time explain the mechanism of apoE4 (1-272) inducing mitochondria fragmentation, leading to neurodegeneration and seeking for the effective target.