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 阿尔茨海默病（AD）是痴呆症的主要原因，影响美国620万人， 全球4400万如果到2050年还找不到治愈方法，这些数字预计将翻两番。广告特征 进行性神经变性开始于海马，导致早期丧失海马- 依赖记忆错误折叠的淀粉样蛋白沉积，这是AD发病前的关键病理标志 痴呆症的几十年，被认为是一个渐进的神经退行性疾病和记忆的启动因素， 损失然而，其潜在机制仍不清楚。在AD早期，淀粉样蛋白沉积伴随着 减少脑血流量。此外，淀粉样蛋白沉积物明显存在于脑微血管系统中， 这导致响应刺激的血管活性受损。这些证据让我们假设 血管淀粉样蛋白损害微血管调节局部血氧输送以满足代谢的能力， 海马体中神经元的需要，导致AD的早期记忆丧失。另外，我们假设淀粉样蛋白- 介导的，神经血管病理驱动的海马记忆力下降是可逆的，改善血液 氧气输送检验这些假设可能为AD发病机制提供新的见解，但需要纵向研究。 对具有已知记忆状态的AD小鼠海马中神经血管功能的显微镜评估， 这在很大程度上超出了常规台式显微镜技术的范围。为了应付这一挑战， 我们建议开发一种双向（成像和操作）光纤接口， 啮齿动物脑深部区域的侵入性评估。结合光声和荧光显微镜， 该装置（直径：230-420 μm）将能够同时成像淀粉样蛋白沉积、微血管功能 （血液氧合和流量）和AD小鼠海马中的神经元活性。此外，根据我们的 最近在基于纤维的深部脑刺激和化学输送方面取得了进展，这种接口也将使病灶 电刺激以评估神经血管耦合和局部输送PGE 2（一种血管扩张剂），以检查 血管平滑肌功能和海马血氧供应是否可恢复以抵消 淀粉样蛋白介导的局灶性缺氧/缺血和改善记忆丧失。总而言之，拟议的研究旨在 建立淀粉样蛋白介导的神经血管功能障碍和记忆之间的直接因果关系 在海马体的损失，其中AD起源，通过开发和应用双向深 大脑接口更广泛地说，改变的神经-血管相互作用和错误折叠的蛋白质聚集已经被发现。 与广泛的脑部疾病相关，包括但不限于AD。实现微观评估 以及对神经元活动、血氧输送和病理分子过程的局部操纵。 无论深度如何，双向深部脑接口预计将在以下方面找到广泛的应用： 基础和转化脑研究。