Department of Neurobiology, Fourth Military Medical University, Xi'an, 710032 Shaanxi, People's Republic of China.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):9094-9102. doi: 10.1073/pnas.1901348116. Epub 2019 Apr 19.
BDNF, an essential trophic factor implicated in synaptic plasticity and neuronal survival, is reduced in Alzheimer's disease (AD). BDNF deficiency's association with Tau pathology in AD is well documented. However, the molecular mechanisms accounting for these events remain incompletely understood. Here we show that BDNF deprivation triggers Tau proteolytic cleavage by activating δ-secretase [i.e., asparagine endopeptidase (AEP)], and the resultant Tau N368 fragment binds TrkB receptors and blocks its neurotrophic signals, inducing neuronal cell death. Knockout of BDNF or TrkB receptors provokes δ-secretase activation via reducing T322 phosphorylation by Akt and subsequent Tau N368 cleavage, inducing AD-like pathology and cognitive dysfunction, which can be restored by expression of uncleavable Tau N255A/N368A mutant. Blocking the Tau N368-TrkB complex using Tau repeat-domain 1 peptide reverses this pathology. Thus, our findings support that BDNF reduction mediates Tau pathology via activating δ-secretase in AD.
脑源性神经营养因子（BDNF）是一种重要的营养因子，参与突触可塑性和神经元存活，在阿尔茨海默病（AD）中减少。BDNF 缺乏与 AD 中的 Tau 病理学的关联已有充分的文献记载。然而，这些事件的分子机制仍不完全清楚。在这里，我们表明 BDNF 的剥夺通过激活 δ-分泌酶（即天冬酰胺内肽酶（AEP））触发 Tau 蛋白的蛋白水解切割，并且所得的 Tau N368 片段结合 TrkB 受体并阻断其神经营养信号，诱导神经元细胞死亡。BDNF 或 TrkB 受体的敲除通过降低 Akt 介导的 T322 磷酸化和随后的 Tau N368 切割来引发 δ-分泌酶的激活，诱导类似 AD 的病理学和认知功能障碍，可通过表达不可切割的 Tau N255A/N368A 突变体来恢复。使用 Tau 重复结构域 1 肽阻断 Tau N368-TrkB 复合物可逆转这种病理。因此，我们的研究结果支持 BDNF 减少通过在 AD 中激活 δ-分泌酶介导 Tau 病理学。
