Low Level Laser Therapy in Alzheimer's Disease

低强度激光治疗阿尔茨海默病

• 批准号: 9493069
• 负责人: Quanguang Zhang
• 金额: $ 125.9万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9493069
• 关键词: Affect; Alzheimer disease prevention; Alzheimer' s Disease; American; Amyloid beta-Protein; Animal Disease Models; Animals; Area; Blood; Blood - brain barrier anatomy; Brain; Brain Diseases; Cause of Death; Chronic; Clinic; Clinical Trials; Cognitive; Data; Dementia; Deposition; Disease; Disease Progression; Extravasation; Functional disorder; Gene Expression; Gene Targeting; Globin; Goals; Heme; Hemoglobin; Homeostasis; Human; Impaired cognition; In Vitro; Inflammation; Inflammatory; Lasers; Lead; Light; Low-Level Laser Therapy; Mitochondria; Modeling; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Nuclear Translocation; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Phototherapy; Plague; Procedures; Rattus; Resistance; Senile Plaques; Signal Pathway; Tauopathies; Testing; Transgenic Organisms; Translations; Treatment Efficacy; United States; Work; abeta accumulation; abeta deposition; abeta toxicity; advanced disease; base; brain tissue; clinically relevant; cognitive benefits; cognitive function; cranium; disability; extracellular; functional outcomes; healing; heme biosynthesis; improved; in vivo; insight; interest; neuroinflammation; neuron loss; neuroprotection; novel; novel therapeutics; pain relief; photobiomodulation; preservation; repaired; restoration; targeted treatment

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.