Jiao S-S, Shen L-L, Zhu C, Bu X-L, Liu Y-H, Liu C-H, Yao X-Q, Zhang L-L, Zhou H-D, Walker D G, Tan J, Götz J, Zhou X-F, Wang Y-J
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
Cadre Ward, Department of Neurology, Bethune International Peace Hospital, Shijiazhuang, China.
Transl Psychiatry. 2016 Oct 4;6(10):e907. doi: 10.1038/tp.2016.186.
Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy.
脑源性神经营养因子（BDNF）表达降低在阿尔茨海默病（AD）的发病机制中起关键作用，AD的特征是由β-淀粉样蛋白（Aβ）组成的神经炎性斑块和由过度磷酸化的tau蛋白组成的神经原纤维缠结的形成。越来越多的证据表明BDNF对AD小鼠模型中Aβ诱导的神经毒性具有潜在的保护作用。然而，BDNF补充剂对AD中tau蛋白病的直接治疗效果仍有待确定。在这里，我们发现AD患者和P301L转基因小鼠（tau蛋白病小鼠模型）的血清和脑中BDNF水平降低。向侧脑室内注射携带编码人BDNF基因的腺相关病毒（AAV-BDNF）可使BDNF基因稳定表达，并恢复P301L小鼠脑中的BDNF水平。BDNF水平恢复可减轻行为缺陷、防止神经元丢失、减轻突触退化并减少神经元异常，但不影响P301L小鼠脑中tau蛋白的过度磷酸化水平。小鼠对脑中AAV-BDNF 的长期表达耐受性良好。这些发现表明，BDNF的基因递送是治疗AD和其他伴有tau蛋白病的神经退行性疾病中tau相关神经变性的一种有前景的治疗方法。
