Blurton-Jones Mathew, Kitazawa Masashi, Martinez-Coria Hilda, Castello Nicholas A, Müller Franz-Josef, Loring Jeanne F, Yamasaki Tritia R, Poon Wayne W, Green Kim N, LaFerla Frank M
Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13594-9. doi: 10.1073/pnas.0901402106. Epub 2009 Jul 24.
Neural stem cell (NSC) transplantation represents an unexplored approach for treating neurodegenerative disorders associated with cognitive decline such as Alzheimer disease (AD). Here, we used aged triple transgenic mice (3xTg-AD) that express pathogenic forms of amyloid precursor protein, presenilin, and tau to investigate the effect of neural stem cell transplantation on AD-related neuropathology and cognitive dysfunction. Interestingly, despite widespread and established Ass plaque and neurofibrillary tangle pathology, hippocampal neural stem cell transplantation rescues the spatial learning and memory deficits in aged 3xTg-AD mice. Remarkably, cognitive function is improved without altering Ass or tau pathology. Instead, the mechanism underlying the improved cognition involves a robust enhancement of hippocampal synaptic density, mediated by brain-derived neurotrophic factor (BDNF). Gain-of-function studies show that recombinant BDNF mimics the beneficial effects of NSC transplantation. Furthermore, loss-of-function studies show that depletion of NSC-derived BDNF fails to improve cognition or restore hippocampal synaptic density. Taken together, our findings demonstrate that neural stem cells can ameliorate complex behavioral deficits associated with widespread Alzheimer disease pathology via BDNF.
神经干细胞（NSC）移植是一种尚未被探索的治疗与认知衰退相关的神经退行性疾病（如阿尔茨海默病（AD））的方法。在这里，我们使用了表达淀粉样前体蛋白、早老素和tau蛋白致病形式的老年三重转基因小鼠（3xTg-AD）来研究神经干细胞移植对AD相关神经病理学和认知功能障碍的影响。有趣的是，尽管存在广泛且已形成的Aβ斑块和神经原纤维缠结病理，但海马神经干细胞移植可挽救老年3xTg-AD小鼠的空间学习和记忆缺陷。值得注意的是，认知功能得到改善，而Aβ或tau病理并未改变。相反，认知改善的潜在机制涉及由脑源性神经营养因子（BDNF）介导的海马突触密度的显著增强。功能获得性研究表明，重组BDNF模拟了NSC移植的有益效果。此外，功能丧失性研究表明，NSC衍生的BDNF的缺失无法改善认知或恢复海马突触密度。综上所述，我们的研究结果表明，神经干细胞可以通过BDNF改善与广泛的阿尔茨海默病病理相关的复杂行为缺陷。
