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

项目总结 阿尔茨海默病(AD)是导致痴呆症的主要原因，影响着美国和美国的620万人 全球有4400万人。如果到2050年还没有找到治疗方法，预计到2050年，这些数字将翻两番。广告功能 从海马区开始的进行性神经退行性变，导致陈述性海马体早期丧失- 从属记忆。错误折叠的淀粉样蛋白沉积，这是发病前阿尔茨海默病的关键病理特征 几十年的痴呆症，被认为是进行性神经变性和记忆的启动因素 损失。然而，潜在的机制仍不清楚。在AD早期，淀粉样蛋白沉积伴随着 脑血流量减少。此外，淀粉样蛋白沉积在脑微血管系统中也很明显， 这会导致对刺激的反应导致血管活性受损。集体证据引导我们提出假设 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 需要海马区的神经元，导致AD的早期记忆丧失。此外，我们假设淀粉样蛋白- 由神经血管病变引起的海马区记忆衰退可通过改善血液状况而逆转 氧气输送。验证这些假说可能会为AD的发病机制提供新的见解，但这需要纵向的 记忆状态已知的AD小鼠海马区神经血管功能的显微评估， 这在很大程度上超出了传统台式显微镜技术的范围。为了应对这一挑战， 我们建议开发一种双向(成像和操纵)光纤接口，用于纵向和最小 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， 该设备(直径：230-420微米)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)，以及AD小鼠海马神经元的活动。此外，在我们的基础上 基于纤维的脑深部刺激和化学输送的最新进展，这一接口也将使焦点 电刺激以评估神经血管偶联和血管扩张剂PGE2的局部释放，以检查 血管平滑肌功能与海马区血氧供应能否恢复抵消 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与记忆的直接和因果关系 通过发展和应用双向深部，AD起源的海马区的损失 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 与多种脑部疾病有关，包括但不限于阿尔茨海默病。启用微观评估 以及对神经元活动、血氧输送和病理分子过程的焦点操纵 啮齿类动物大脑不分深度，双向脑深部接口有望在 基础脑研究和转化脑研究。

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.