In tauopathies, phosphorylation, acetylation, cleavage and other modifications of tau drive intracellular generation of diverse forms of toxic tau aggregates and associated seeding activity, which have been implicated in subsequent synaptic failure and neurodegeneration. Suppression of this wide range of pathogenic species, seeding and toxicity mechanisms, while preserving the physiological roles of tau, presents a key therapeutic goal. Identification and targeting of signaling networks that influence a broad spectrum of tau pathogenic mechanisms might prevent or reverse synaptic degeneration and modify disease outcomes. The p75 neurotrophin receptor (p75NTR) modulates such networks, including activation of multiple tau kinases, calpain and rhoA-cofilin activity. The orally bioavailable small-molecule p75NTR modulator, LM11A-31, was administered to tauP301S mice for 3 months starting at 6 months of age, when tau pathology was well established. LM11A-31 was found to reduce: excess activation of hippocampal cdk5 and JNK kinases and calpain; excess cofilin phosphorylation, tau phosphorylation, acetylation and cleavage; accumulation of multiple forms of insoluble tau aggregates and filaments; and, microglial activation. Hippocampal extracts from treated mice had substantially reduced tau seeding activity. LM11A-31 treatment also led to a reversal of pyramidal neuron dendritic spine loss, decreased loss of dendritic complexity and improvement in performance of hippocampal behaviors. These studies identify a therapeutically tractable upstream signaling module regulating a wide spectrum of basic mechanisms underlying tauopathies.

中文翻译：

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p75神经营养蛋白受体的小分子调节可抑制p301S tauopathy小鼠的多种tau分子病理及其后遗症。

在tauopathies，tau的磷酸化，乙酰化，裂解和其他修饰驱动细胞内生成多种形式的有毒tau聚集体和相关的播种活性，这与随后的突触衰竭和神经变性有关。抑制这种广泛的致病物种，播种和毒性机制，同时保留tau的生理作用，是一个关键的治疗目标。识别和靶向影响广泛的tau致病机制的信号网络可能预防或逆转突触变性并改变疾病结局。p75神经营养蛋白受体（p75NTR）调节这种网络，包括激活多个tau激酶，钙蛋白酶和rhoA-cofilin活性。口服生物利用小分子p75NTR调节剂LM11A-31，当tau病理良好时，从6个月大时开始对tauP301S小鼠进行3个月的给药。发现LM11A-31减少：海马cdk5和JNK激酶及钙蛋白酶的过度活化；过度的cofilin磷酸化，tau磷酸化，乙酰化和裂解; 多种形式的不溶性tau聚集体和细丝的积累；小胶质细胞活化。来自处理过的小鼠的海马提取物的tau接种活性大大降低。LM11A-31治疗还导致了锥体神经元树突棘丧失的逆转，树突复杂性丧失的减少以及海马行为表现的改善。这些研究确定了可治疗的上游信号转导模块，可调节多种潜在的病理机制。