新的阿尔兹海默病基因修饰小鼠模型的构建与表型分析

Progressive loss of hippocampus and cortex is one of pathological hallmarks of AD. However, unlike human AD patients, none of transgenic models of AD mimic massive neuronal loss in the hippocampus and cotex. APP can be degraded through non-amyloidogenic way by α- secretase or amyloidogenic way by β- secretase and γ-secretase. Our previous study found that, in contrast to hunman, mouse hippocampal neuronal cell bodies express high levels of α-secretase but low levels of β-secretase and γ-secretase. These findings suggest that no massive neuronal loss in transgenic models of AD mouse is related to the neuroprotective role of α-secretase. Based on this, we plan to establish 3xTg/ADAM10–/– transgenic mouse to better fully simulate pathology of AD，through 3xTg mice crossed with neuronal specific ADAM10–/–mice, and further clarify the molecular mechanism of α-,β- and γ-secretases regulating the neuronal fate in AD transgenic mice. The potential results would help to deepen our understanding the pathogenesis of AD and providing a high quality platform for preclinical therapeutic evaluation of AD.

AD的特征性病理改变是皮质和海马神经元进行性丢失。然而，与人类AD患者不同，现有的AD转基因鼠模型并无皮质和海马大量神经元丢失。APP的降解分为α-分泌酶介导的非淀粉样肽源途径和β-、γ-分泌酶介导的淀粉样肽源途径。我们前期研究发现：与人类相反，小鼠海马神经元胞体相对高水平表达α-分泌酶，相对低水平表达β-、γ-分泌酶。这提示，目前AD转基因鼠无大量神经元丢失可能与α-分泌酶的保护作用有关。因此，本课题拟通过3xTg小鼠与神经元特异性ADAM10–/–小鼠杂交，构建能较全面模拟AD病理变化的3xTg/ADAM10–/–小鼠，并进一步阐明α-、β-、γ-分泌酶调控AD转基因小鼠神经元命运的分子机制。预期结果有望深化对AD发病机理的认识，并有助于高质量的AD临床前药效学评价技术平台的建设。