Low Level Laser Therapy in Alzheimer's Disease

摘要 阿尔茨海默病(AD)是美国最常见的痴呆症，影响着500多万人 美国人。不幸的是，目前还没有有效的治疗策略来减缓、阻止或逆转 疾病的进展。作为一种非侵入性程序，低强度激光治疗(LLLT)或 光生物调节被广泛用于刺激愈合、减轻疼痛和减少炎症。我们的 AD动物模型的前期研究及一种新型临床相关转基因动物的初步资料 大鼠模型研究表明，LLLT对AD的病理特征和认知功能有较强的保护作用 拒绝。这一令人兴奋的观察结果使人们希望LLLT对AD的神经保护作用的进一步研究 可能会为人类带来新的治疗方法。当前提案的总体目标是测试 LLLT对AD病理的神经保护和认知改善作用及其机制 机械装置。我们假设血液中的血红蛋白(血液-Hb)通过 AD进展过程中受损的血脑屏障聚集形成β鼠疫，增强 氧化应激和炎症，并加速紧张症。除此之外，AD诱导的线粒体 碎裂和能量消耗，以及神经元血红蛋白(Neu-Hb)的减少，都会减弱 细胞对β毒性的抵抗力。总体而言，AD诱导细胞外Aβ沉积，细胞内异常 线粒体分裂和功能障碍，神经原纤维缠结，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方面的益处。我们假设这些好处源于 LLLT保存健康线粒体分裂/融合动力学的能力，从而促进线粒体 功能，以及促进内源性血红素的生物合成。此外，我们还提出了LLLT诱导 线粒体动力学的改变将加强缺氧诱导因子-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血脑屏障损伤，从而 减少外源性血液-Hb加剧的A-β聚集。另一方面，缺氧诱导因子-1α诱导的珠蛋白 可以与线粒体产生的血红素组装形成Neu-Hb，发挥有益的作用。这个 拟议的研究将通过确定LLLT对保护 广告大脑。特定目标1将检验LLLT发挥神经保护和改善 转基因AD大鼠的功能结局。具体目标2将检验这样一种假设，即保存 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。 特定目标3将测试LLLT减少Aβ聚集和增加神经元的假设 AD病理条件下线粒体-缺氧诱导因子-1、α-Hb通路的激活导致抵抗/内稳态。

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.