Neuroscience Center, University of Helsinki, Helsinki, Finland.
PLoS One. 2013 Jul 3;8(7):e68722. doi: 10.1371/journal.pone.0068722. Print 2013.
Brain-derived neurotrophic factor (BDNF) importantly regulates learning and memory and supports the survival of injured neurons. Reduced BDNF levels have been detected in the brains of Alzheimer's disease (AD) patients but the exact role of BDNF in the pathophysiology of the disorder remains obscure. We have recently shown that reduced signaling of BDNF receptor TrkB aggravates memory impairment in APPswe/PS1dE9 (APdE9) mice, a model of AD. The present study examined the influence of Bdnf gene deficiency (heterozygous knockout) on spatial learning, spontaneous exploratory activity and motor coordination/balance in middle-aged male and female APdE9 mice. We also studied brain BDNF protein levels in APdE9 mice in different ages showing progressive amyloid pathology. Both APdE9 and Bdnf mutations impaired spatial learning in males and showed a similar trend in females. Importantly, the effect was additive, so that double mutant mice performed the worst. However, APdE9 and Bdnf mutations influenced spontaneous locomotion in contrasting ways, such that locomotor hyperactivity observed in APdE9 mice was normalized by Bdnf deficiency. Obesity associated with Bdnf deficiency did not account for the reduced hyperactivity in double mutant mice. Bdnf deficiency did not alter amyloid plaque formation in APdE9 mice. Before plaque formation (3 months), BDNF protein levels where either reduced (female) or unaltered (male) in the APdE9 mouse cortex. Unexpectedly, this was followed by an age-dependent increase in mature BDNF protein. Bdnf mRNA and phospho-TrkB levels remained unaltered in the cortical tissue samples of middle-aged APdE9 mice. Immunohistological studies revealed increased BDNF immunoreactivity around amyloid plaques indicating that the plaques may sequester BDNF protein and prevent it from activating TrkB. If similar BDNF accumulation happens in human AD brains, it would suggest that functional BDNF levels in the AD brains are even lower than reported, which could partially contribute to learning and memory problems of AD patients.
脑源性神经营养因子（BDNF）对学习和记忆具有重要的调节作用，并能支持受损神经元的存活。阿尔茨海默病（AD）患者的大脑中检测到 BDNF 水平降低，但 BDNF 在该疾病病理生理学中的确切作用仍然不清楚。我们最近表明，BDNF 受体 TrkB 的信号转导减少会加重 APPswe/PS1dE9（APdE9）小鼠，即 AD 模型中的记忆障碍。本研究检测了 Bdnf 基因缺失（杂合敲除）对中年雄性和雌性 APdE9 小鼠的空间学习、自发探索活动和运动协调/平衡的影响。我们还研究了在不同年龄的具有进行性淀粉样蛋白病理的 APdE9 小鼠中的大脑 BDNF 蛋白水平。APdE9 和 Bdnf 突变均损害了雄性动物的空间学习，并且在雌性动物中显示出相似的趋势。重要的是，这种影响具有累加性，因此双突变小鼠的表现最差。然而，APdE9 和 Bdnf 突变以相反的方式影响自发运动，APdE9 小鼠中观察到的运动过度活跃通过 Bdnf 缺乏而正常化。与 Bdnf 缺乏相关的肥胖症并不能解释双突变小鼠的运动过度活跃减少。Bdnf 缺乏并未改变 APdE9 小鼠中的淀粉样斑块形成。在斑块形成之前（3 个月），APdE9 小鼠皮层中的 BDNF 蛋白水平降低（雌性）或不变（雄性）。出乎意料的是，随后出现成熟 BDNF 蛋白的年龄依赖性增加。在中年 APdE9 小鼠的皮质组织样本中，Bdnf mRNA 和磷酸化-TrkB 水平保持不变。免疫组织化学研究显示，淀粉样斑块周围的 BDNF 免疫反应性增加，表明斑块可能隔离 BDNF 蛋白并阻止其激活 TrkB。如果类似的 BDNF 积累发生在人类 AD 大脑中，这表明 AD 大脑中的功能性 BDNF 水平甚至比报道的还要低，这可能部分导致 AD 患者的学习和记忆问题。
