Low Level Laser Therapy in Alzheimer's Disease

低强度激光治疗阿尔茨海默病

基本信息

  • 批准号:
    9493069
  • 负责人:
  • 金额:
    $ 125.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-07-15 至 2021-08-18
  • 项目状态:
    已结题

项目摘要

ABSTRACT Alzheimer’s disease (AD) is the most common form of dementia in the United States, affecting over 5 million Americans. Unfortunately, there are currently no effective therapeutic strategies to slow, halt, or reverse the advance of the disease. As a noninvasive procedure, Low-level Laser Therapy (LLLT) or photobiomodulation is widely practiced to stimulate healing, relieve pain, and reduce inflammation. Our previous studies on AD animal models and our preliminary data on a novel and clinically relevant transgenic rat model have shown that LLLT can strongly protect against AD pathological hallmarks and cognitive decline. This exciting observation has led to hope that further studies of LLLT neuroprotection against AD could potentially lead to new therapies in humans. The overall goal of the current proposal is to test the neuroprotective and cognitive improvement effects of LLLT on AD pathology, and to elucidate the underlying mechanisms. We hypothesize that leakage of blood hemoglobin (blood-Hb) into brain tissue through the compromised blood brain barrier (BBB) during AD progression aggregates Aβ plague formation, enhances oxidative stress and inflammation, and accelerates tauopathy. Alongside this, AD-induced mitochondrial fragmentation and energy depletion, as well as decreases in neuronal hemoglobin (Neu-Hb), weakens cellular resistance to Aβ toxicity. Collectively, AD induces extracellular Aβ deposits, aberrant intracellular mitochondrial fission and dysfunction, neurofibrillary tangles, and oxidative and inflammatory damage that ultimately culminate in neurodegeneration and cognitive decline. However, we hypothesize that LLLT can confer neuroprotective and cognitive benefits in AD pathology. We posit that these benefits result from LLLT’s ability to preserve healthy mitochondrial fission/fusion dynamics, thereby promoting mitochondrial function as well as enhancing endogenous heme biosynthesis. In addition, we propose that LLLT induced shifts in mitochondrial dynamics will potentiate nuclear translocation of HIF-1α to induce the target gene expression. On the one hand, the induced factors are able to protect and repair BBB damage, thereby reducing Aβ aggregation exacerbated by exogenous blood-Hb. On the other hand, HIF-1α-induced globin can be assembled with mitochondrial-produced heme to form Neu-Hb to exert beneficial effects. The proposed studies would advance the field by determining the potential efficacy of LLLT for protection of the AD brain. Specific Aim 1 would test the hypothesis that LLLT exerts neuroprotection and improves functional outcome in transgenic AD rats. Specific Aim 2 would test the hypothesis that preservation of mitochondrial dynamics and restoration of mitochondrial function underlies LLLT’s neuroprotective abilities. Specific Aim 3 would test the hypothesis that LLLT reduces Aβ aggregation and increases neuronal resistance/homeostasis via the activation of Mitochondria-HIF-1α-Hb pathway in AD pathological conditions.
摘要 阿尔茨海默病(AD)是美国最常见的痴呆症,影响超过500万人。 美国人不幸的是,目前还没有有效的治疗策略来减缓、停止或逆转这种疾病。 疾病的进展。作为一种非侵入性手术,低水平激光治疗(LLLT)或 光生物调节被广泛用于刺激愈合、缓解疼痛和减少炎症。我们 先前关于AD动物模型的研究和我们关于一种新的和临床相关的转基因的初步数据 大鼠模型已经显示LLLT可以强烈地保护AD病理标志和认知功能, 下降这一令人兴奋的观察结果带来了希望,进一步研究LLLT对AD的神经保护作用 可能会为人类带来新的治疗方法。目前提案的总体目标是测试 LLLT对AD病理学的神经保护和认知改善作用,并阐明其潜在的 机制等我们假设血液血红蛋白(blood-Hb)通过脑组织渗漏到脑组织中, AD进展期间受损的血脑屏障(BBB)聚集Aβ斑块形成,增强Aβ斑块形成, 氧化应激和炎症,并加速tau蛋白病。除此之外,AD诱导的线粒体 碎片和能量消耗,以及神经元血红蛋白(Neu-Hb)的减少, 细胞对Aβ毒性的抵抗力。总的来说,AD诱导细胞外Aβ沉积,异常细胞内Aβ沉积, 线粒体分裂和功能障碍,神经细胞缠结,以及氧化和炎症损伤, 最终导致神经退化和认知能力下降。然而,我们假设LLLT可以 在AD病理学中赋予神经保护和认知益处。我们认为这些好处来自于 LLLT能够保持健康的线粒体分裂/融合动力学,从而促进线粒体 功能以及增强内源性血红素生物合成。此外,我们认为LLLT诱导了 线粒体动力学的改变将增强HIF-1α的核转位,以诱导靶基因 表情一方面,诱导因子能够保护和修复BBB损伤, 降低外源性血红蛋白加重的Aβ聚集。另一方面,HIF-1α诱导的珠蛋白 可与体内产生的血红素组装形成Neu-Hb发挥有益作用。的 拟议的研究将通过确定LLLT对保护 AD大脑。具体目标1将检验LLLT发挥神经保护作用并改善神经功能的假设。 转基因AD大鼠的功能结果。具体目标2将检验这样一个假设,即保护 线粒体动力学和线粒体功能的恢复是LLLT神经保护能力的基础。 具体目标3将检验LLLT减少Aβ聚集并增加神经元聚集的假设。 AD病理状态下通过激活线粒体-HIF-1α-Hb通路的抵抗/稳态。

项目成果

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Quanguang Zhang其他文献

Quanguang Zhang的其他文献

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{{ truncateString('Quanguang Zhang', 18)}}的其他基金

Low-level Laser Therapy in Global Cerebral Ischemia
低强度激光治疗全球性脑缺血
  • 批准号:
    8816362
  • 财政年份:
    2014
  • 资助金额:
    $ 125.9万
  • 项目类别:

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  • 财政年份:
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