神经营养因子受体 p75 介导淀粉样 β 诱导的 tau 病理。

Neurotrophin receptor p75 mediates amyloid β-induced tau pathology.

机构信息

Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing 400042, China; Chongqing Key Laboratory of Aging and Brain Diseases, Chongqing 400042, China; Shigatse Branch, Xinqiao Hospital, Third Military Medical University, Shigatse 857000, China.

出版信息

Neurobiol Dis. 2019 Dec;132:104567. doi: 10.1016/j.nbd.2019.104567. Epub 2019 Aug 5.

DOI:10.1016/j.nbd.2019.104567

PMID:31394202

Abstract

Neurofibrillary tangles of hyperphosphorylated tau protein (p-tau) are a key pathological feature of Alzheimer's disease (AD). Tau phosphorylation is suggested to be secondary to amyloid-beta (Aβ) accumulation. However, the mechanism by which Aβ induces tau phosphorylation in neurons remains unclear. Neurotrophin receptor p75 (p75) is a receptor for Aβ and mediates Aβ neurotoxicity, implying that p75 may mediate Aβ-induced tau phosphorylation in AD. Here, we showed that Aβ-induced tau hyperphosphorylation and neurodegeneration, including tau phosphorylation, synaptic disorder and neuronal loss, in the brains of both male wild-type (Wt) mice and male P301L transgenic mice (a mouse model of human tauopathy) were alleviated by genetic knockout of p75 in the both mouse models. We further confirmed that the activation or inhibition of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase-3β (GSK3β) significantly changed Aβ/p75-mediated p-tau levels in neurons. Treatment of male P301L mice with soluble p75 extracellular domain (p75ECD-Fc), which antagonizes the binding of Aβ to p75, suppressed tau hyperphosphorylation. Taken together, our findings suggest that p75 meditates Aβ-induced tau pathology and is a potential druggable target for AD and other tauopathies.

摘要

神经原纤维缠结是高度磷酸化的 tau 蛋白（p-tau）的一种关键病理学特征，也是阿尔茨海默病（AD）的主要病理学特征之一。tau 蛋白磷酸化被认为继发于淀粉样β（Aβ）的积累。然而，Aβ 如何在神经元中诱导 tau 磷酸化的机制尚不清楚。神经生长因子受体 p75（p75）是 Aβ的受体，介导 Aβ 神经毒性，这意味着 p75 可能在 AD 中介导 Aβ 诱导的 tau 磷酸化。在这里，我们发现 Aβ 诱导的 tau 过度磷酸化和神经退行性变，包括 tau 磷酸化、突触紊乱和神经元丢失，在雄性野生型（Wt）小鼠和雄性 P301L 转基因小鼠（一种人类 tau 病的小鼠模型）的大脑中，p75 在这两种小鼠模型中的基因敲除都减轻了 tau 过度磷酸化和神经退行性变。我们进一步证实，周期蛋白依赖性激酶 5（CDK5）和糖原合酶激酶 3β（GSK3β）的激活或抑制显著改变了神经元中 Aβ/p75 介导的 p-tau 水平。用可溶性 p75 细胞外结构域（p75ECD-Fc）治疗雄性 P301L 小鼠，该物质拮抗 Aβ 与 p75 的结合，抑制 tau 过度磷酸化。总之，我们的研究结果表明，p75 介导 Aβ 诱导的 tau 病理学，是 AD 和其他 tau 病的潜在治疗靶点。