A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression.
A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression.
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DOI：
10.1371/journal.pone.0102136
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Longo FM
中科院分区：
文献类型：
--
作者：
Simmons DA;Knowles JK;Belichenko NP;Banerjee G;Finkle C;Massa SM;Longo FM
基底前脑胆碱能神经元的退化对阿尔茨海默病（AD）相关的认知缺陷有重要作用，并可归因于通过神经营养因子受体p75 （p75NTR）发出的异常信号。因此，调节p75NTR信号被认为是一种很有前途的治疗AD的策略。因此，我们的实验室在体外研究中开发了小分子p75NTR配体，可增加存活信号并抑制淀粉样蛋白β诱导的退行性信号传导。先前的研究发现，在疾病病理的早期阶段给予AD小鼠模型时，先导p75NTR配体LM11A-31可以防止胆碱能神经突的退化。为了扩大其潜在的临床应用，我们试图确定LM11A-31是否可以逆转中晚期AD小鼠模型在开始治疗时的胆碱能神经萎缩。逆转病理可能具有特殊的临床相关性，因为大多数阿尔茨海默病研究涉及到处于晚期病理阶段的患者。在本研究中，将LM11A-31（50或75 mg/kg）口服给两只AD小鼠模型，Thy-1 hAPPLond/Swe （APPL/S）和Tg2576，在有明显AD样病理表现的年龄范围内。在中期雄性APPL/S小鼠中，从6-8月龄开始给予LM11A-31 3个月，可以预防和/或逆转基底前脑胆碱能神经突和皮质营养不良神经突的萎缩。重要的是，对患有晚期病理的雄性APPL/S小鼠（12-13月龄）给予1个月的LM11A-31治疗，逆转了基底前脑胆碱能神经突的退化，改善了皮质营养不良神经突，并使基底前脑p75NTR水平升高正常化。在雌性Tg2576小鼠中也看到了类似的结果。这些发现表明LM11A-31可以减少和/或逆转晚期AD小鼠的基础AD病理。因此，靶向p75NTR是一种很有希望的方法，可以减少ad相关的退行性过程，这些退行性过程已经超过了早期阶段。
Degeneration of basal forebrain cholinergic neurons contributes significantly to the cognitive deficits associated with Alzheimer's disease (AD) and has been attributed to aberrant signaling through the neurotrophin receptor p75 (p75NTR). Thus, modulating p75NTR signaling is considered a promising therapeutic strategy for AD. Accordingly, our laboratory has developed small molecule p75NTR ligands that increase survival signaling and inhibit amyloid-β-induced degenerative signaling in in vitro studies. Previous work found that a lead p75NTR ligand, LM11A-31, prevents degeneration of cholinergic neurites when given to an AD mouse model in the early stages of disease pathology. To extend its potential clinical applications, we sought to determine whether LM11A-31 could reverse cholinergic neurite atrophy when treatment begins in AD mouse models having mid- to late stages of pathology. Reversing pathology may have particular clinical relevance as most AD studies involve patients that are at an advanced pathological stage. In this study, LM11A-31 (50 or 75 mg/kg) was administered orally to two AD mouse models, Thy-1 hAPPLond/Swe (APPL/S) and Tg2576, at age ranges during which marked AD-like pathology manifests. In mid-stage male APPL/S mice, LM11A-31 administered for 3 months starting at 6–8 months of age prevented and/or reversed atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites. Importantly, a 1 month LM11A-31 treatment given to male APPL/S mice (12–13 months old) with late-stage pathology reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages.
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影响因子：
2.9
作者：
King, DL;Arendash, GW
通讯作者：
Arendash, GW
影响因子：
3.5
作者：
Fahnestock, M;Michalski, B;Coughlin, MD
通讯作者：
Coughlin, MD
影响因子：
2.9
作者：
BUELL, SJ;COLEMAN, PD
通讯作者：
COLEMAN, PD
DOI：
10.1016/0169-328x(89)90073-9
发表时间：
1989-12-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
GIBBS, RB;MCCABE, JT;PFAFF, DW
通讯作者：
PFAFF, DW
影响因子：
64.5
作者：
Huang Y;Mucke L
通讯作者：
Mucke L