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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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，其特征是 β 淀粉样蛋白 (Ab) 斑块和神经原纤维缠结的神经病理性积聚包括来自多个小组的最新数据支持，只要有足够的时间，Ab 和 tau 就会扩散。沿着大脑网络以明确的方式遍及整个大脑，与朊病毒蛋白的传播方式非常相似值得注意的是，据报道，嗅觉系统是最先受到影响的系统之一。 AD。我们过去的工作重点是使用锰增强 MRI (MEMRI) 来评估轴突运输。 AD 小鼠模型中的嗅觉系统事实上，我们已经报道了嗅觉中的轴突运输缺陷。系统在学习和记忆缺陷出现之前以及斑块形成之前就可以检测到。这些数据与 AD 病理从大脑开始扩散到整个大脑的观点是一致的。此外，我们之前的工作还集中于减少氧化应激的影响。当我们通过过度表达超氧化物歧化酶 2 (SOD-2) 来减少氧化应激时，AD 小鼠模型。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 50% 以上。尽管氧化应激已被确定为 AD 发展的重要因素，但努力减少氧化应激抗氧化剂对抗氧化应激的效果有限，部分原因被认为是这样的。包括无法将足够数量的抗氧化剂注射到适当的区域此外，临床上可用的抗氧化剂溶解度差，不易进入细胞。我们已经转向纳米技术，并一直在研究更有效的纳米抗氧化剂与临床上可用的抗氧化剂相比，它无毒且易于进入细胞。使用鼻内施用的纳米抗氧化剂（PEG-HCC）保护嗅觉和邻近结构将通过行为分析、MEMRI、静息态功能磁共振成像 (rs-fMRI) 评估，减缓 AD 的进展以及 31P 测量和组织学，我们还将结合机器学习，特别是概率学。图形模型，以确定 AD 和 AD 小鼠模型中目标 1 和 2 中读数的相互作用我们还建议结合机器学习来预测。 1) 应降低超氧化物水平以改善 AD 病理学；2) AD 的哪个阶段（例如斑块前与斑块后）是无法挽救的，完成这个高度创新的项目将具有重大意义。影响 AD 治疗策略的未来。