老年痴呆症患者大脑内存在大量神经元缺失，可能的原因包括神经元死亡增加或者神经再生障碍，最近的研究显示哺乳动物大脑内仍然存在活跃的神经再生，研究显示AD模型小鼠脑内存在神经再生的障碍。Wnt信号通路与神经增殖和再生密切相关，白血病染色体1融合基因 AF1Q高度表达于中枢神经系统，但其功能未知。我们的初步结果显示AF1Q在模型小鼠脑内表达减低，高表达AF1Q能够促进体外培养的神经干细胞增殖并抑制其分化，AF1Q能够激活Wnt信号通路，其分子机制与AF1Q促进TCF7的稳定性和核转入相关，因此我们假设AF1q通过Wnt信号通 路调控NSCs的增殖并参与AD发生。本课题中将进一步明确AF1q激活Wnt信号通路的分子机制， 检测AF1Q-TCF7相互作用对AD模型小鼠神经干细胞增殖和分化的影响，以及在AD小鼠脑内表达A F1Q观察对其对痴呆症发生的作用，此研究将为神经干细胞治疗AD提供理论依据。

Alzheimer’s Disease is the most common neurodegenerative disorder leading to dementia. There is extensive neuronal loss in AD brains. The neuronal loss was either due to the increase of neuronal death or impairment of neurogenesis. Active neurogenesis has been found in mammalian brains. Wnt signaling has been shown to be involved in neurodevelopment and neurogenesis. ALL1-fused from chromosome 1q (AF1Q), originally considered as an oncogenic factor, has been implicated in the pathogenesis of neurodegeneration. AF1Q is highly expressed during neurodevelopment, but its specific functions in neural system remained elusive. Our preliminary study demonstrated that AF1Q facilitated neural stem cell proliferation. AF1q could induce cell proliferation by activating Wnt signaling pathway. Reporter assay showed AF1Q could activate Wnt signaling. And co-immunoprecipitation (CO-IP) analysis demonstrated that AF1q bound specifically to T-cell factor/lymphoid enhancer binding factor-7 (TCF/LEF7), which stabilized TCF7 and facilitated TCF7 translocation into nucleus. Thus, we hypothesize that AF1Q regulate TCF7-Wnt signaling, which facilitated AD pathogenesis in AD mice. This grant application will continue to investigate the interaction of AF1Q and TCF7 as well as its involvement in AD pathogenesis by addressing the following specific aims:.Aim 1: To further examine the molecular mechanism by which AF1Q regulates TCF7-Wnt.. Aim 2: To examine how AF1Q-TCF7 interaction affects the proliferation and differentiation of neural stem cells from AD mice. Aim 3: To examine if AF1Q expression in mice affects neurogenesis and AD pathogenesis..Our study here identified AF1Q as an important factor in neurodevelopment by interacting with TCF7 and regulating WNT signaling pathway. The study will explore the putative therapeutic effect of using AAV9 to upregulate AF1Q in AD mice.