Departments of Neurosciences and Pathology, University of California, San Diego, La Jolla, California 92093-0624.
J Neurosci. 2010 Sep 15;30(37):12252-62. doi: 10.1523/JNEUROSCI.1305-10.2010.
During aging and in the progression of Alzheimer's disease (AD), synaptic plasticity and neuronal integrity are disturbed. In addition to the alterations in plasticity in mature neurons, the neurodegenerative process in AD has been shown to be accompanied by alterations in neurogenesis. Members of the bone morphogenetic protein (BMP) family of growth factors have been implicated as important regulators of neurogenesis and neuronal cell fate determination during development; however, their role in adult neurogenesis and in AD is less clear. We show here by qRT-PCR analysis that BMP6 mRNA levels were significantly increased in the hippocampus of human patients with AD and in APP transgenic mice compared to controls. Immunoblot and immunohistochemical analyses confirmed that BMP6 protein levels were increased in human AD brains and APP transgenic mouse brains compared to controls and accumulated around hippocampal plaques. The increased levels of BMP6 were accompanied by defects in hippocampal neurogenesis in AD patients and APP transgenic mice. In support of a role for BMP6 in defective neurogenesis in AD, we show in an in vitro model of adult neurogenesis that treatment with amyloid-β(1-42) protein (Aβ) resulted in increased expression of BMP6, and that exposure to recombinant BMP6 resulted in reduced proliferation with no toxic effects. Together, these results suggest that Aβ-associated increases in BMP6 expression in AD may have deleterious effects on neurogenesis in the hippocampus, and therapeutic approaches could focus on normalization of BMP6 levels to protect against AD-related neurogenic deficits.
在衰老和阿尔茨海默病（AD）的进展过程中，突触可塑性和神经元完整性受到干扰。除了成熟神经元可塑性的改变外，AD 的神经退行性过程还伴随着神经发生的改变。骨形态发生蛋白（BMP）家族的生长因子成员已被证明是发育过程中神经发生和神经元细胞命运决定的重要调节因子；然而，它们在成人神经发生和 AD 中的作用尚不清楚。我们通过 qRT-PCR 分析显示，与对照组相比，AD 患者和 APP 转基因小鼠的海马体中 BMP6 mRNA 水平显著增加。免疫印迹和免疫组织化学分析证实，与对照组相比，BMP6 蛋白水平在 AD 大脑和 APP 转基因小鼠大脑中增加，并在海马体斑块周围积累。BMP6 水平的增加伴随着 AD 患者和 APP 转基因小鼠海马体神经发生缺陷。为了支持 BMP6 在 AD 中神经发生缺陷中的作用，我们在成人神经发生的体外模型中表明，淀粉样蛋白-β（1-42）蛋白（Aβ）的处理导致 BMP6 的表达增加，而暴露于重组 BMP6 导致增殖减少，没有毒性作用。总之，这些结果表明，AD 中与 Aβ 相关的 BMP6 表达增加可能对海马体的神经发生产生有害影响，治疗方法可以集中在正常化 BMP6 水平以防止 AD 相关的神经发生缺陷。
