Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AβPP(L/S) transgenic mice.
Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AβPP(L/S) transgenic mice.
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DOI：
10.3233/jad-140036
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
Longo FM
中科院分区：
文献类型：
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作者：
Nguyen TV;Shen L;Vander Griend L;Quach LN;Belichenko NP;Saw N;Yang T;Shamloo M;Wyss-Coray T;Massa SM;Longo FM
p75 神经营养素受体 (p75NTR ) 参与与阿尔茨海默病 (AD) 相关的退行性机制。此外，p75NTR 水平在 AD 中升高，并且该受体由在该疾病中特别脆弱的神经元表达。因此，调节 p75NTR 功能可能是一种重要的疾病缓解治疗方法。先前的研究表明，非肽小分子 p75NTR 配体 LM11A-31 和化学上不相关的 LM11A-24 可以在体外阻断淀粉样蛋白 β 诱导的有害信号传导和神经变性，并且发现 LM11A-31 可以减轻 AD 小鼠模型中的神经炎变性和行为缺陷。在本研究中，我们通过检查 LM11A-24 效应来确定这些体内发现是否代表 p75NTR 配体的类别效应。此外，通过评估 tau 病理学和神经炎症进一步检查了化合物作用的范围。口服给药后，两种配体均达到已知可在体外提供神经保护的脑浓度。 p75NTR 裂解的复合诱导为 CNS 靶标参与提供了证据。 LM11A-31和LM11A-24减少了tau蛋白的过度磷酸化，LM11A-31也抑制了其异常折叠。两种配体均减少小胶质细胞的活化，而 LM11A-31 则减弱反应性星形胶质细胞。随着炎症反应的减少，两种配体都减少了胆碱能神经突变性。除了改善 AD 模型小鼠的神经病理学之外，LM11A-31（而非 LM11A-24）还可以防止水迷宫性能受损，而两种配体都可以防止恐惧条件反射的缺陷。这些发现支持 p75NTR 配体在预防 AD 中与 tau 相关的基本病理机制中的作用，并进一步验证了这些小分子作为一类新型治疗化合物的开发。
The p75 neurotrophin receptor (p75NTR ) is involved in degenerative mechanisms related to Alzheimer’s disease (AD). In addition, p75NTR levels are increased in AD and the receptor is expressed by neurons that are particularly vulnerable in the disease. Therefore, modulating p75NTR function may be a significant disease-modifying treatment approach. Prior studies indicated that the non-peptide, small molecule p75NTR ligands LM11A-31, and chemically unrelated LM11A-24, could block amyloid-β-induced deleterious signaling and neurodegeneration in vitro, and LM11A-31 was found to mitigate neuritic degeneration and behavioral deficits in a mouse model of AD. In this study, we determined whether these in vivo findings represent class effects of p75NTR ligands by examining LM11A-24 effects. In addition, the range of compound effects was further examined by evaluating tau pathology and neuroinflammation. Following oral administration, both ligands reached brain concentrations known to provide neuroprotection in vitro. Compound induction of p75NTR cleavage provided evidence for CNS target engagement. LM11A-31 and LM11A-24 reduced excessive phosphorylation of tau, and LM11A-31 also inhibited its aberrant folding. Both ligands decreased activation of microglia, while LM11A-31 attenuated reactive astrocytes. Along with decreased inflammatory responses, both ligands reduced cholinergic neurite degeneration. In addition to the amelioration of neuropathology in AD model mice, LM11A-31, but not LM11A-24, prevented impairments in water maze performance, while both ligands prevented deficits in fear conditioning. These findings support a role for p75NTR ligands in preventing fundamental tau-related pathologic mechanisms in AD, and further validate the development of these small molecules as a new class of therapeutic compounds.