国内外研究和我们前期结果均显示神经元内apoE4(1-272)是真正的致AD病变分子，可导致tau蛋白过度磷酸化，但机制不清。我们前期研究发现神经元内apoE4(1-272)可激活Caspase-2诱发高尔基体破碎。高尔基体是糖基化修饰的重要细胞器，高尔基体破碎可促使O糖基化酶GalNAc-T2的分布改变；而糖基化异常的tau更易被磷酸化。另外Caspase-2可剪切基质蛋白，引发高尔基体破碎。因此提出：apoE4(1-272) 可通过激活Caspase-2剪切基质蛋白，诱发高尔基体破碎，导致tau糖基化酶分布、活性异常，促使tau糖基化异常，进而引起tau过度磷酸化。拟在前期建立的apoE4(1-272)转基因鼠和四环素可调控的apoE4(1-272)表达的细胞模型，综合运用超微病理、形态、分子生物学等手段研究上述科学问题。为深入研究apoE4(1-272)导致AD病理变化提供依据。

Our previous results show that apoE4 hydrolysis fragments (1-272) is the key molecular marker of neurodegeneration in Alzheimer's disease (AD), which can lead to hyperphosphorylation of tau in neurons，but the molecular mechanism is not clear. Golgi fragmentation has been found in the early stage of AD and does not depend on the stability of the cytoskeleton. Our previous results showed that apoE4 (1-272) fragments induced Golgi fragmentation by activating Caspase-2 in neurons. Golgi is the important organelle of glycosylation. Golgi fragmentation can induce the N-acetyl galactose aminotransferase 2 (GalNAc-T2) abnormal distributions while the increase of the N-glycosylation and the reduction of O-glycosylation could more easily induce tau phosphorylation. Caspase-2 could degrade Golgi matrix proteins and trigger Golgi fragmentation. Thus, apoE4(1-272) through activation of Caspase-2-induced Golgi fragmentation may promote tau glycosylation abnormalities, in turn caused tau hyperphosphorylation. 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 Golgi fragmentation, leading to tau hyperphosphorylation and seeking for the effective target.