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首页> 外文学位 >Molecular Mechanisms of Alzheimer's Cerebral Amyloidosis: A Preclinical Study of Latrepirdine as a Prospective Alzheimer's Therapeutic.
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Molecular Mechanisms of Alzheimer's Cerebral Amyloidosis: A Preclinical Study of Latrepirdine as a Prospective Alzheimer's Therapeutic.

机译：阿尔茨海默氏病脑淀粉样变性的分子机制：拉特哌丁作为阿尔茨海默氏症治疗药物的临床前研究。

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摘要

Age-dependent decrease in basal neuronal turnover of autophagic substrates has been identified as a neuropathology associated with the progression of Alzheimer's disease. However, the relationship between the onset of autophagic/lysosomal arrest and accumulation of APP/Abeta remains to be determined. Here, we report that onset of behavioral impairment, along with the accumulation in mouse brain of soluble oligomeric Abeta (oAbeta) and insoluble Abeta42 and p62 at 3 months of age precedes the accumulation autophagic/lysosomal substrates, including alpha-synclein, LC3, and p62 at 4 months of age. Using two novel mouse lines, we determined that accumulation of soluble oAbeta, not insoluble Abeta42 and p62, results in behavioral memory impairment. We provide evidence that oAbeta levels determine cognitive status, and that insoluble Abeta42 and p62 accumulation precedes autophagic/lysosomal arrest in mouse models of Alzheimer's cerebral amyloidosis.;Latrepirdine is a neuroactive compound with antagonist activity at histaminergic, alpha-adrenergic, and serotonergic receptors. We hypothesized that modulation of macroautophagy might be a relevant mechanism of latrepirdine action that would provide a parsimonious explanation for the various drug-dependent anti-proteotoxicity phenomena that have been reported. We present evidence that latrepirdine (1) enhances autophagy via an mTOR- and Atg5-dependent mechanism; (2) stimulates both degradation and secretion of APP metabolites; (3) protects against alpha-synuclein cytotoxicity in yeast and mammalian cells; and (4) does not protect against the cytotoxicity of TDP-43, FUS, or huntingtin.;Acute latrepirdine administration significantly increased secretion of Abeta40 in the hippocampus of freely-moving Tg2576 mice and latrepirdine therapy for 3 weeks enhanced autophagy in the brains of both wild-type mice and young, pre-plaque TgCRND8 mice, in agreement with our cell culture experiments. Chronic latrepirdine administration for 31 days to 3-month-old TgCRND8 mice was associated with enhanced autophagy, improved learning behavior and retarded accumulation of autophagic substrates, including APP metabolites, alpha-synuclein, and the polyubiquitin-binding protein p62. We conclude that latrepirdine possesses pro-autophagic, antiproteotoxic properties that are relevant to treatment and/or prevention of neurodegenerative diseases, especially those involving accumulation of Abeta and/or alpha-synuclein. We propose that latrepirdine represents a potentially viable lead compound that might yield more consistent clinical benefit following optimization of its pro-cognitive and pro-autophagic activities.
机译：自噬基质的基底神经元更新的年龄依赖性减少已被确定为与阿尔茨海默氏病进展相关的神经病理学。然而，自噬/溶酶体停滞的发作与APP / Abeta的积累之间的关系仍有待确定。在这里，我们报告说，行为障碍的发作以及3个月大时在小鼠脑中的可溶性寡聚Abeta（oAbeta）和不溶性Abe​​ta42和p62的积累先于自噬/溶酶体底物的积累，包括α-synclein，LC3和4个月大时为p62。使用两种新颖的小鼠系，我们确定了可溶性oAbeta而不是不溶性Abe​​ta42和p62的积累会导致行为记忆障碍。我们提供的证据表明oAbeta水平决定了认知状态，在阿尔茨海默氏脑淀粉样变性的小鼠模型中，不溶性Abe​​ta42和p62积累先于自噬/溶酶体逮捕。;拉特哌丁是一种对组胺能，α-肾上腺素能和血清素能受体具有拮抗活性的神经活性化合物。我们假设，巨噬细胞自噬的调节可能是拉特吡啶作用的一种相关机制，这将为已报道的各种药物依赖性抗蛋白毒性现象提供一个简洁的解释。我们提供的证据表明，拉美吡丁（1）通过依赖mTOR和Atg5的机制增强自噬； （2）刺激APP代谢物的降解和分泌； （3）防止酵母和哺乳动物细胞中α-突触核蛋白的细胞毒性； （4）不能抵抗TDP-43，FUS或亨廷顿蛋白的细胞毒性。急性拉提普汀给药可显着增加自由移动的Tg2576小鼠海马中Abeta40的分泌，拉提哌啶治疗3周可增强脑内自噬。野生型小鼠和斑块前年轻的TgCRND8小鼠均与我们的细胞培养实验一致。对3个月大的TgCRND8小鼠进行31天的长期latrepirdine给药与自噬增强，学习行为改善和自噬底物（包括APP代谢产物，α-突触核蛋白和多泛素结合蛋白p62）的积聚有关。我们得出的结论是，latrepirdine具有与治疗和/或预防神经退行性疾病（尤其是涉及Abeta和/或α-突触核蛋白积聚的神经退行性疾病）有关的前自噬，抗蛋白毒性特性。我们建议，拉特吡丁代表潜在的可行的先导化合物，在优化其前认知和前自噬活性后可能产生更一致的临床益处。

著录项

  • 作者

    Steele, John W., IV.;

  • 作者单位

    Mount Sinai School of Medicine.;

  • 授予单位 Mount Sinai School of Medicine.;
  • 学科 Biology Molecular.;Biology Cell.;Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 274 p.
  • 总页数 274
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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