近日，美国亚利桑那州太阳城老年健康研究所华人科学家申勇博士等发现，阿尔茨海默病（AD）患者的祖细胞生成神经元的能力受限，可能是由于β连接素（β catenin）信号转导通路被β淀粉样蛋白（Aβ）干扰。相关论文发表于美国《神经科学杂志》（J Neurosci 2009，29（20）：6545）。
AD可破坏大脑的神经元，影响人的认知功能。虽然近来研究显示，健康人新皮质中的祖细胞可以“生产”新生神经元，但AD患者的祖细胞是否有此功能，尚不可知。
申勇博士等通过比较健康对照者和AD患者皮质中的胶质祖细胞（GPC），发现AD患者的GPC更新能力和神经发生能力减弱。进一步研究发现，与健康对照者相比，AD患者的GPC中糖原合酶激酶3β（GSK-3β，一种可催化β连接素磷酸化的酶——编者注）水平更高，而且伴随着磷酸化β连接素的水平升高。用Aβ处理健康对照者的GPC，可使其生成新生神经元的能力丧失，还导致β连接素的信号转导蛋白发生变化，与AD患者脑中所见相同。
申勇博士认为，该结果说明，取自AD患者脑皮质的干细胞可能不具有神经发生的能力，因而无法用于AD的治疗。但β连接素的信号转导通路与神经发生有关，或许可成为治疗AD的靶点。（生物谷Bioon.com）
The Journal of Neuroscience, May 20, 2009, 29(20):6545-6557; doi:10.1523/JNEUROSCI.0421-09.2009
Interruption of β-Catenin Signaling Reduces Neurogenesis in Alzheimer's Disease
Ping He and Yong Shen
Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, Arizona 85351
The neuronal loss associated with Alzheimer's disease (AD) affects areas of the brain that are vital to cognition. Although recent studies have shown that new neurons can be generated from progenitor cells in the neocortices of healthy s, the neurogenic potential of the stem/progenitor cells of AD patients is not known. To answer this question, we compared the properties of glial progenitor cells (GPCs) from the cortices of healthy control (HC) and AD subjects. The GPCs from AD brain samples displayed reduced renewal capability and reduced neurogenesis compared with GPCs from HC brains. To investigate the mechanis underlying this difference, we compared β-catenin signaling proteins in GPCs from AD versus HC subjects and studied the effect of amyloid β peptide (Aβ, a hallmark of AD pathology) on GPCs. Interestingly, GPCs from AD patients exhibited elevated levels of glycogen synthase kinase 3β (GSK-3β, an enzyme known to phosphorylate β-catenin), accompanied by an increase in phosphorylated β-catenin and a decrease in nonphosphorylated β-catenin compared with HC counterparts. Furthermore. we found that Aβ treatment impaired the ability of GPCs from HC subjects to generate new neurons and caused changes in β-catenin signaling proteins similar to those observed in GPCs from AD patients. Similar results were observed in GPCs isolated from AD transgenic mice. These results suggest that Aβ-induced interruption of β-catenin signaling may contribute to the impairment of neurogenesis in AD progenitor cells.
