脑老化阿尔茨海默病（AD）引发的学习能力下降与部分记忆的丧失所涉及的分子机制仍未阐明。本课题组前期的工作发现电压门控性钠离子通道2型beta亚基(Navβ2)的表达抑制通过调节海马神经元兴奋性、改变APP酶解方向而显著改善老年AD转基因小鼠学习记忆能力，而miR-449a靶向调控Navβ2。为探讨Navβ2在认知功能减退进展过程中的作用及其调控机制，本课题组拟通过轻度认知功能减退（MCI）及AD转基因动物模型，MCI、AD及临床前AD患者外周血与脑脊液标本，运用多项检测技术开展以下研究：1）探究Navβ2在脑老化认知功能减退不同阶段中的可能作用；2）探讨miR-449a是否通过对Navβ2的调控参与了早期MCI向AD全面认知功能减退的进展过程；3）初探miR-449a/Navβ2在临床前AD、MCI及AD患者认知功能减退中的诊断价值。本研究将为脑老化认知功能减退的早期防治提供新思路。

Brain senescence associated diseases, Alzheimer's disease (AD), often leads to learning deficits and memory deterioration. However, the underlying cellular and molecular mechanisms have not been elucidated. Current clinical progress for the prevention and treatment of brain senescence is also far from being satisfactory. Our previous data revealed that a downregulation of Navβ2 in Navβ2-knockdown mice resulted in improving the hippocampus-dependent cognitive function and facilitating hippocampal long-term potentiation by improving neuronal activity and decreasing Aβ deposition. However, the mechanism underlying Navβ2 expression regulation is still unknown. Our recently work revealed that miR-449a targeted Navβ2 coded mRNA. Therefore, we propose that aberrant expression and dysfunction of Navβ2, regulated by miR-449a, may play an important role in the aging-related cognitive deterioration. In the present study, by employing mild cognitive impairment (MCI) and AD transgenic mice, primary hippocampus neurons, plasma and cerebrospinal fluid (CSF) of AD and preclinical AD (PAD) patients, we will determine: 1) the possible roles of Navβ2 in different stages of cognitive impairment deterioration from MCI to AD dementia; 2) whether miR-449a affects cognitive impairment deterioration by targeting Navβ2 in MCI and AD mice; 3) the potential diagnosis values of miR-449a and Navβ2 in cognitive impairment of preclinical PAD, MCI and AD patients. The present study could provide the strategy of candidate target to develop potential biomarkers and anti-senescence drugs for the treatment of brain aging at the early stage.