A bidirectional deep brain interface to unravel the pathogenic role of vascular amyloid in Alzheimer's disease

双向深部脑接口揭示血管淀粉样蛋白在阿尔茨海默病中的致病作用

• 批准号: 10901002
• 负责人: Song Hu
• 金额: $ 79.53万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901002
• 关键词: Address; Affect; Age Months; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Amyloid deposition; Animal Behavior; Behavior; Behavioral; Blood; Blood Vessels; Brain; Brain Diseases; Brain Hypoxia-Ischemia; Brain region; Cerebrovascular Circulation; Chemicals; Chronic; Cognition; Control Groups; Deep Brain Stimulation; Dementia; Deposition; Development; Devices; Diameter; Dinoprostone; Disease; Disease Progression; Electric Stimulation; Electrodes; Engineering; Ensure; Evaluation; Fiber; Fluorescence Microscopy; Functional disorder; Hippocampus; Histopathology; Hyperemia; Hypoxia; Image; Impaired cognition; Impairment; Implant; Individual; Light; Link; Longitudinal Studies; Mediating; Memory; Memory Loss; Metabolic; Metals; Methods; Microfluidics; Microscopic; Microscopy; Modality; Molecular; Mus; Nerve Degeneration; Neurons; Neurosciences; Oxygen; Pathogenesis; Pathogenicity; Pathologic; Pathology; Penetration; Peptide Initiation Factors; Persons; Process; Rodent; Role; Stimulus; Structure; Symptoms; Techniques; Testing; Time; Ultrasonics; United States; Vascular Diseases; Vascular Smooth Muscle; Vasodilator Agents; amyloid imaging; behavior test; biomaterial compatibility; brain research; cerebral microvasculature; design; implantation; improved; in vivo; insight; meter; microendoscope; minimally invasive; misfolded protein; mouse model; neural; neurovascular; neurovascular coupling; progressive neurodegeneration; protein aggregation; response; three photon microscopy

PROJECT SUMMARY Alzheimer’s disease (AD) is the leading cause of dementia, affecting 6.2 million people in the United States and 44 million worldwide. These numbers are expected to quadruple by 2050, if no cure is found by then. AD features progressive neurodegeneration beginning in the hippocampus, leading to early loss of declarative hippocampal- dependent memory. The deposition of misfolded amyloid, a key pathological hallmark of AD preceding the onset of dementia by decades, is believed to be an initiating factor of the progressive neurodegeneration and memory loss. However, the underlying mechanisms remain unclear. Early in AD, amyloid deposition is accompanied by reduction of cerebral blood flow. Also, amyloid deposits are conspicuously found on the brain microvasculature, which results in impaired vasoactivity in response to stimulation. The collective evidence leads us to hypothesize that vascular amyloid impairs microvessel’s ability to regulate local blood oxygen delivery to meet the metabolic need of neurons in the hippocampus, causing early memory loss in AD. Further, we hypothesize that the amyloid- mediated, neurovascular pathology-driven memory decline in the hippocampus is reversible with improved blood oxygen delivery. Testing the hypotheses may offer new insights into AD pathogenesis, but it requires longitudinal microscopic assessments of neurovascular function in the hippocampus of AD mice with known memory status, which is largely beyond the reach of conventional benchtop microscopy techniques. To address this challenge, we propose to develop a bidirectional (imaging and manipulation) fiber interface for longitudinal and minimally invasive assessments of deep brain regions in rodents. Combining photoacoustic and fluorescence microscopy, this device (diameter: 230–420 µm) will enable concurrent imaging of amyloid deposition, microvascular function (blood oxygenation and flow), and neuronal activity in the hippocampus of AD mice. Moreover, building upon our recent progress in fiber-based deep brain stimulation and chemical delivery, this interface will also enable focal electrical stimulation to assess neurovascular coupling and local delivery of PGE2, a vasodilator, to examine the function of vascular smooth muscles and whether hippocampal blood oxygen supply is retrievable to counteract the amyloid-mediated focal hypoxia/ischemia and improve memory loss. In summary, the proposed study seeks to establish the direct and causal relationship between amyloid-mediated neurovascular dysfunction and memory loss in the hippocampus, where AD originates, through the development and application of a bidirectional deep brain interface. More broadly, altered neural-vascular interaction and misfolded protein aggregation have been associated with a wide range of brain diseases, including but not limited to AD. Enabling microscopic assessment and focal manipulation of neuronal activity, blood oxygen delivery, and pathological molecular processes in the rodent brain irrespective of depth, the bidirectional deep brain interface is expected to find broad applications in basic and translational brain research.

项目摘要 阿尔茨海默氏病（AD）是痴呆症的主要原因，影响了美国的620万人 全球4400万。如果届时找不到治疗，这些数字有望在2050年到2050年四倍。广告功能 从海马开始的进行性神经变性，导致宣告海马的早期丧失 相关内存。错误折叠淀粉样蛋白的沉积，这是发作之前广告的关键病理标志 数十年来的痴呆症被认为是进行性神经退行性的开始因素 损失。但是，基本机制尚不清楚。在AD的早期，淀粉样蛋白沉积是由 减少脑血流。此外，在大脑微脉管系统上明显发现淀粉样蛋白沉积物， 这会导致响应刺激的血管活性受损。集体证据使我们假设 该血管淀粉样蛋白会损害微血管调节局部血氧递送以满足代谢的能力 海马中神经元的需求，导致AD的早期记忆力丧失。此外，我们假设淀粉样蛋白 介导的，神经血管病理驱动的海马的记忆下降是可逆的，有改善的血液 氧递送。检验假设可能会为AD发病机理提供新的见解，但需要纵向 对具有已知记忆状态的AD小鼠海马中神经血管功能的微观评估， 这在很大程度上超出了传统的台式显微镜技术的范围。为了应对这个挑战， 我们建议开发双向（成像和操纵）纤维界面，以进行纵向和最小 啮齿动物中深脑区域的侵入性评估。结合光声和荧光显微镜， 该设备（直径：230–420 µm）将同时进行淀粉样蛋白沉积，微血管功能 （血液氧合和流动）以及AD小鼠海马中的神经元活性。而且，在我们的基础上 基于纤维的深脑刺激和化学递送的最新进展，该界面也将使局灶性 电刺激评估血管扩张剂PGE2的神经血管耦合和局部递送，以检查 血管平滑肌肉的功能以及海马血氧供应是否可以取回 淀粉样蛋白介导的局灶性缺氧/缺血并改善记忆力丧失。总而言之，拟议的研究寻求 建立淀粉样蛋白介导的神经血管功能障碍与记忆的直接和因果关系 通过双向深处的开发和应用，海马的损失，AD起源于AD的损失 脑接口。更广泛地，神经 - 血管相互作用和错误折叠的蛋白质聚集已经改变了 与广泛的脑部疾病有关，包括但不限于AD。启用微观评估 以及对神经元活性，血氧递送和病理分子过程的局灶性操纵 啮齿动物大脑不论深度如何，双向深脑界面有望在 基本和翻译的大脑研究。