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.

项目概要 阿尔茨海默病 (AD) 是导致痴呆症的主要原因，影响着美国 620 万人， 全球 4400 万。如果到 2050 年还没有找到治愈方法，预计这一数字将翻两番。广告功能 从海马体开始进行性神经变性，导致声明性海马体早期丧失 依赖记忆。错误折叠淀粉样蛋白的沉积是 AD 发病前的一个关键病理标志 痴呆症发病数十年，被认为是进行性神经退行性变和记忆的起始因素 损失。然而，其根本机制仍不清楚。 AD 早期，淀粉样蛋白沉积伴随着 脑血流量减少。此外，在大脑微血管系统上也明显发现淀粉样蛋白沉积物， 这导致对刺激的反应受损的血管活性。集体证据使我们做出假设 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 海马体神经元的需求，导致 AD 早期记忆丧失。此外，我们假设淀粉样蛋白 海马体介导的、神经血管病理驱动的记忆力下降是可逆的，且血液状况改善 氧气输送。检验这些假设可能会为 AD 发病机制提供新的见解，但需要纵向研究 对已知记忆状态的 AD 小鼠海马神经血管功能进行显微镜评估， 这在很大程度上超出了传统台式显微镜技术的能力范围。为了应对这一挑战， 我们建议开发一种双向（成像和操作）光纤接口，用于纵向和最小化 对啮齿动物深部大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）将能够同时对淀粉样蛋白沉积、微血管功能进行成像 （血氧和流量）以及 AD 小鼠海马体中的神经元活动。此外，在我们的基础上 基于纤维的深部脑刺激和化学输送的最新进展，该接口也将使焦点 电刺激以评估神经血管耦合和 PGE2（一种血管扩张剂）的局部递送，以检查 血管平滑肌的功能以及海马血氧供应是否可以恢复以抵消 淀粉样蛋白介导的局灶性缺氧/缺血并改善记忆丧失。总之，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与记忆之间的直接因果关系 通过开发和应用双向深部神经元，可以消除阿尔茨海默病的发源地——海马体的损失。 大脑接口。更广泛地说，神经血管相互作用的改变和错误折叠的蛋白质聚集已被 与多种脑部疾病相关，包括但不限于AD。实现微观评估 以及神经元活动、血氧输送和病理分子过程的局部操纵 无论啮齿动物的大脑深度如何，双向深脑接口有望在以下领域找到广泛的应用： 基础和转化脑研究。