Delaying Alzheimer's Disease Progression Through Intranasally Administered Nano-Antioxidants

通过鼻内给予纳米抗氧化剂延缓阿尔茨海默病的进展

• 批准号: 10395142
• 负责人: ROBIA G PAUTLER
• 金额: $ 73万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395142
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Animals; Antioxidants; Axonal Transport; Bayesian Network; Behavioral Assay; Biological; Brain; Cells; Clinical; Data; Development; Disease; Disease Progression; Dose; Functional Magnetic Resonance Imaging; Future; Health; Histologic; Histology; Image; Intranasal Administration; Learning; Machine Learning; Magnetic Resonance Imaging; Manganese; Measurement; Memory; Memory impairment; Methods; Mission; Modeling; Molecular; Mus; Nanotechnology; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Olfactory Pathways; Oxidative Stress; Pathology; Phase; Phosphocreatine; PrP; Public Health; Recovery; Reporting; Research; Rest; Role; SOD2 gene; Senile Plaques; Solubility; Structure; Superoxides; Support Groups; System; Testing; Time; Travel; United States National Institutes of Health; Work; abeta accumulation; awake; behavior influence; disorder control; hyperphosphorylated tau; improved; innovation; mouse model; nano; neuroimaging; novel; overexpression; prevent; sensory system; success; tau Proteins; time use

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the neuropathological accumulation of amyloid beta (Ab) plaques and neurofibrillary tangles comprised of hyperphosphorylated tau. Recent data from multiple groups support that given enough time, Ab and tau spreads throughout the brain in a well-defined manner along brain networks, very similar to the way a prion protein travels throughout the brain. Notably, the olfactory system has been reported to be one of the first systems affected in AD. Our past work has focused on using Manganese Enhanced MRI (MEMRI) to assess axonal transport in the olfactory system in mouse models of AD. Indeed, we have reported that axonal transport deficits in the olfactory system are detectable prior to the development of learning and memory deficits and well before plaque formation. These data are consistent with the idea that AD pathology spreads throughout the brain, beginning with the olfactory system. Additionally, our prior work has also focused on the effects of reducing oxidative stress in mouse models of AD. When we reduced oxidative stress by overexpressing superoxide dismutase 2 (SOD-2) in mouse models of AD, we observed a complete recovery in learning and memory deficits, a complete recovery in axonal transport deficits in the olfactory system as well as an over 50% reduction in Ab plaque formation. Although oxidative stress has been identified as a significant player in the development of AD, efforts to reduce oxidative stress with antioxidants has met with limited success. Some of the reasons for this are thought to include the inability to target sufficient quantities of administered antioxidants to the appropriate regions within the brain. Additionally, clinically available antioxidants have poor solubility and do not readily enter cells. Thus, we have turned to nanotechnology and have been working with nano-antioxidants that are much more potent than clinically available antioxidants, are non-toxic and readily enter cells. We therefore hypothesize that protecting olfactory and adjoining structures with intranasally administered nano-antioxidants (PEG-HCCs) will slow down the progression of AD as assessed with behavioral assays, MEMRI, resting state fMRI (rs-fMRI) as well as 31P measurements and histology. We will also incorporate machine learning, specifically, a probabilistic graphical model, to determine the interactions of the readouts in Aims 1 and 2 in mouse models of AD and controls with and without treatment with PEG-HCCs. We also propose to incorporate machine learning to predict 1) the degree to which superoxide levels should be reduced to improve AD pathology and 2) which stages of AD (e.g. pre vs post plaque) are beyond rescue. Completion of this highly innovative project will have significant impact towards future AD therapeutic strategies.

阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征在于： β淀粉样蛋白（Ab）斑块和神经纤维缠结的神经病理学积累，包括 过度磷酸化的tau蛋白来自多个研究小组的最新数据支持，如果有足够的时间，Ab和tau的传播 沿着大脑网络以明确的方式遍布大脑，非常类似于朊病毒蛋白的传播方式 在整个大脑中。值得注意的是，据报道，嗅觉系统是第一个受到影响的系统之一， AD.我们过去的工作主要集中在使用锰增强MRI（MEMRI）来评估轴突运输， 嗅觉系统在AD小鼠模型中的作用事实上，我们已经报道，轴突运输赤字在嗅觉 在学习和记忆缺陷的发展之前以及在斑块形成之前可以检测到系统。 这些数据与AD病理学在整个大脑中传播的想法一致，从大脑开始， 嗅觉系统此外，我们先前的工作也集中在减少氧化应激的影响， AD小鼠模型。当我们通过过表达超氧化物歧化酶2（SOD-2） 在AD小鼠模型中，我们观察到学习和记忆缺陷完全恢复， 嗅觉系统中轴突运输缺陷以及Ab斑块形成减少超过50%。 虽然氧化应激已被确定为AD发展中的重要参与者，但减少氧化应激的努力仍然存在。 抗氧化剂的氧化应激效果有限。其中一些原因被认为是 包括不能将足够量的施用的抗氧化剂靶向到体内的适当区域 大脑此外，临床上可用的抗氧化剂具有差的溶解度，并且不容易进入细胞。因此，在本发明中， 我们已经转向纳米技术，并一直在研究纳米抗氧化剂， 比临床上可用的抗氧化剂，是无毒的，容易进入细胞。因此，我们假设， 用鼻内施用的纳米抗氧化剂（PEG-HCCs）保护嗅觉和邻近结构， 通过行为测定、MEMRI、静息状态fMRI（rs-fMRI）评估，减缓AD的进展， 以及31 P测量和组织学。我们还将纳入机器学习，特别是概率学习 图形模型，以确定AD小鼠模型中目标1和2中读数的相互作用， 用和不用PEG-HCC处理的对照。我们还建议结合机器学习来预测 1)超氧化物水平应降低到何种程度以改善AD病理学和2）AD的哪些阶段 (e.g.斑块形成前与斑块形成后）是无法挽救的。这一极具创新性的项目的完成将产生重大影响。 对未来AD治疗策略的影响。