The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau
The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau
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ProNGF/p75NTR 通路可诱导 tau 病理，是 FTLD-tau 的治疗靶点。
DOI：
10.1038/s41380-018-0071-z
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发表时间：
2018-08-01
影响因子：
11
通讯作者：
Wang, Yan-Jiang
中科院分区：
文献类型：
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作者：
Shen, Lin-Lin;Manucat-Tan, Noralyn B.;Wang, Yan-Jiang
陶氏病理被归类为一种额颞叶变性（FTLD）形式，即FTLD - 陶氏病。潜在的致病机制尚不清楚，目前也没有可用的治疗干预措施。在此，我们报道神经营养因子受体p75NTR在FTLD - 陶氏病的发病机制中起关键作用。在FTLD - 陶氏病患者和小鼠（P301L转基因）的大脑中，p75NTR和神经生长因子前体（proNGF）的表达增加。在体外，proNGF通过p75NTR诱导陶氏蛋白磷酸化，这与AKT/糖原合成酶激酶（GSK）3β通路相关。在P301L小鼠中减少p75NTR基因表达可挽救记忆缺陷，减轻陶氏蛋白过度磷酸化，并恢复AKT/GSK3β通路的活性。用可溶性p75NTR胞外域（p75ECD - Fc）治疗P301L小鼠，该物质可拮抗p75NTR的神经毒性配体，能有效改善记忆行为并抑制陶氏病理。这表明p75NTR在陶氏病理中起关键作用，并代表了FTLD - 陶氏病及相关陶氏蛋白病的一个潜在药物作用靶点。
Tau pathology is characterized as a form of frontotemporal lobar degeneration (FTLD) known as FTLD-tau. The underlying pathogenic mechanisms are not known and no therapeutic interventions are currently available. Here, we report that the neurotrophin receptor p75NTR plays a critical role in the pathogenesis of FTLD-tau. The expression of p75NTR and the precursor of nerve growth factor (proNGF) were increased in the brains of FTLD-tau patients and mice (P301L transgenic). ProNGF-induced tau phosphorylation via p75NTR in vitro, which was associated with the AKT/glycogen synthase kinase (GSK)3 beta pathway. Genetic reduction of p75NTR in P301L mice rescued the memory deficits, alleviated tau hyperphosphorylation and restored the activity of the AKT/GSK3 beta pathway. Treatment of the P301L mice with the soluble p75NTR extracellular domain (p75ECD-Fc), which can antagonize neurotoxic ligands of p75NTR, effectively improved memory behavior and suppressed tau pathology. This suggests that p75NTR plays a crucial role in tau paGSKthology and represents a potential druggable target for FTLD-tau and related tauopathies.