Rescuing neurovascular coupling to protect neuronal plasticity and cognition

摘要 越来越多的证据表明，脑微循环改变对认知障碍和 阿尔茨海默病(AD)和AD相关痴呆(ADRD)中观察到的痴呆症。然而，缺乏方法 对小脑血管的成像和对其功能的研究阻碍了我们对其认识的进步 血管性认知损害和痴呆(VCID)的病理序列。最早的AD和AD的迹象 患者和小鼠模型中的VCID通常涉及空间和短期记忆缺陷-认知 海马区突触可塑性所维持的功能。神经元的能量有限 储备并因此依赖于“即时”神经血管耦合(NVC)策略，在NVC策略中，活动区域发出信号 以局部扩张和增加局部血流量。阿尔茨海默病患者和小鼠模型 CADASIL是VCID的单基因原型形式，显示出NVC的早期恶化。我们之前的研究已经 确定了毛细血管内皮细胞中起作用的分子缺陷，并开发了一种治疗方法 能显著恢复AD和CADASIL小鼠模型的NVC。具体地说，我们发现全身注射 磷脂PIP2足以通过使Kir2.1通道作为神经血管的感受器来修复神经血管缺陷 外源性K的增加--神经元活动的产物--并将其转化为血管扩张剂电信号 它迅速传播到上游小动脉，推动血管扩张，产生局部充血。我们的 多学科团队，在脑微循环和脑部微循环的前沿成像方面具有互补的专业知识 学习和记忆过程中的突触可塑性，将检验NVC恢复将 缓解海马区突触可塑性的恶化及其行为后果 广告。我们进一步建议研究和比较CADASIL中的这些功能，CADASIL是血管驱动的ADRD形式。 为了实现这一目标，我们将推进基于PIP2的策略，在AD和CADASIL中长期恢复NVC 模型，并通过开发创新的体外成像方法来评估治疗效率，具有一种新的 本课题组建立了完整的毛细血管-小动脉(CAPA)制备方法，并采用植入分级指数的方法进行体内实验 (GRIN)透镜结合双光子显微镜研究海马区的NVC。最终，我们会 NVC挽救对AD和CADASIL所致海马区突触可塑性恶化的影响 条件，并使用情境恐惧条件作用作为行为读数。完成这项研究将有助于澄清 AD/ADRDS中NVC功能障碍与痴呆的联系机制，以及NVC恢复作为一种潜在的治疗方法。 这项拟议的工作有可能为大脑微循环如何维持提供一种范式转换的观点。 学习和记忆过程。

Summary Growing evidence points towards the contribution of altered brain microcirculation to cognitive impairment and dementia observed in Alzheimer’s disease (AD) and AD-related dementia (ADRD). Yet, the lack of approaches to image the small cerebrovasculature and investigate its function has hampered our progress in understanding the pathological sequence of vascular cognitive impairment and dementia (VCID). The earliest signs of AD and VCID in patients and mouse models typically involve deficits in spatial and short-term memory—cognitive functions that are critically sustained by synaptic plasticity in the hippocampus. Neurons have limited energy reserves and thus rely on a “just-in-time” neurovascular coupling (NVC) strategy in which active regions signal to the microvasculature to locally dilate and increase local blood flow. Patients and mouse models of AD or CADASIL, a monogenic archetypal form of VCID, show an early deterioration in NVC. Our previous studies have identified a molecular defect at play in capillary endothelial cells and developed a therapeutic approach that acutely restores NVC in the mouse model of AD and CADASIL. Specifically, we found that systemic injection of phospholipid PIP2 is sufficient to rescue neurovascular deficits by enabling Kir2.1 channels to act as sensors of increases in external K+—a product of neuronal activity—and transduce this into a vasodilator electrical signal that rapidly propagates to upstream arterioles, driving vasodilation to produce local hyperemia. Our multidisciplinary team, with complementary expertise in cutting-edge imaging of brain microcirculation and synaptic plasticity underlying learning and memory processes, will test the hypothesis that NVC restoration will mitigate the synaptic plasticity deterioration in the hippocampus, and its behavioral consequences, observed in AD. We further propose to investigate and compare these functions in CADASIL, a vascular driven form of ADRD. To attain this goal, we will advance our PIP2-based strategy to chronically restore NVC in AD and CADASIL models, and assess the treatment efficiency by developing innovative imaging approaches ex vivo, with a novel intact capillary-arteriolar (CaPA) preparation established by our group, and in vivo using implanted graded-index (GRIN) lenses combined with 2-photon microscopy to investigate NVC in the hippocampus. Ultimately, we will measure the effect of NVC rescue on hippocampal synaptic plasticity deterioration caused by AD and CADASIL conditions, and use contextual fear conditioning as a behavioral readout. Completing this study will help elucidate the mechanisms linking NVC dysfunction to dementia in AD/ADRDs, and NVC restoration as a potential therapy. The proposed work has the potential to provide a paradigm-shifting view on how brain microcirculation sustains learning and memory processes.