Metabolic and neural activity normalization by cerebral blood flow increase in AD/ADRD models

AD/ADRD 模型中脑血流量增加使代谢和神经活动正常化

• 批准号: 10657935
• 负责人: CHRIS B SCHAFFER
• 金额: $ 117.03万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657935
• 关键词: Acceleration; Address; Aftercare; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Antibodies; Apolipoprotein E; Behavior; Biological Markers; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Pathology; Cardiovascular system; Cell physiology; Cellular Metabolic Process; Cerebrovascular Circulation; Cerebrum; Cessation of life; Dependence; Disease; Disease Progression; Drops; Electrodes; Electrophysiology (science); Exhibits; Future; Genes; Genetic Models; Goals; Grant; Hippocampus; Hour; Human; Hyperactivity; Hypertension; Hypoxia; Impaired cognition; Incidence; Injections; Investigation; Label; Link; Measurement; Measures; Memory; Memory impairment; Metabolic; Metabolism; Modeling; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Nutrient; Obstruction; Optics; Oxygen; Pathogenicity; Pathologic Processes; Patients; Pattern; Performance; Perfusion; Platelet Inhibitors; Predictive Factor; Process; Protein Overexpression; Proteins; Receptor Cell; Recovery; Recovery of Function; Research Personnel; Secondary to; Severities; Short-Term Memory; Silicon; Speed; Stimulus; Stroke; Symptoms; Techniques; Testing; Therapeutic; Time; Tissues; Viral; Visual Cortex; Wild Type Mouse; Work; apolipoprotein E-4; brain dysfunction; brain metabolism; brain tissue; cardiovascular risk factor; cell injury; cerebral capillary; cognitive function; cognitive recovery; dementia risk; excitatory neuron; functional outcomes; genetic risk factor; hypertensive; improved; in vivo calcium imaging; inhibitory neuron; insight; memory consolidation; metabolic rate; middle age; mouse model; neural; neural circuit; neural network; neuronal patterning; neutrophil; response; restoration; sex; spatial memory; stressor; tissue oxygenation; vascular risk factor

SUMMARY Although many biomarkers have been identified in AD/ADRD, the most important effect is cognitive function. Links between AD/ADRD symptoms and cerebral blood flow deficits or vascular risk factors such as hypertension are well recognized in patients, but the mechanisms are still under investigation. In mouse models of AD about 2% of capillaries are occluded by an arrested neutrophil and these stalled capillaries have a profound effect on cerebral blood flow. Such capillary stall perfusion deficits (CSPD) could reduce oxygenation and nutrient delivery to neurons and are therefore potential drivers of cognitive dysfunction in AD/ADRD. In AD mouse models, working memory performance is rescued within hours of reducing the incidence of stalled capillaries to increase cerebral blood flow using antibodies against the neutrophil protein Ly6G. CSPD has also been observed in a new non-amyloid ADRD model, hypertensive mice with targeted replacement of the murine ApoE gene with the AD-promoting ApoE4 human allele. In this mouse, rapid rescue of behavior and flow are observed after treatment with the platelet inhibitor prasugrel, suggesting a different cellular cause of CSPD than that observed in the AD models. The rapid time scales of cognitive recovery are too fast for many pathological processes and rule out vascular or neural remodeling. Instead, the speed of memory improvement suggests that changes in the dynamic firing pattern of neurons underlie the rescue and that improved metabolic support by increased cerebral blood flow is a critical factor in determining the functionality of neural circuits. This suggests that slower processes such as protein accumulation and remodeling can be secondary to fast effects linked to improvement of oxygen and metabolite delivery after blood flow increase. This proposal tests the idea that cerebral blood flow recovery leads to corrections in blood oxygenation and in oxygen usage, which then result in metabolic and cellular functional recovery in neurons (Aim 1). Such metabolic changes are hypothesized to underly corrections of aberrant neural activity that ultimately determine behavior. Aim 1 will use gamma oscillations, coordinated neural activity associated with healthy cortical function, as a simultaneous measure of the consequence of the oxygenation changes. In AD mouse models, an imbalance in the activity of inhibitory and excitatory neurons results in reduced fidelity of neural encoding of stimuli. Aim 2 asks if the blood flow improvement also corrects this activity imbalance and improves the precision of stimulus encoding for orientation tuned neurons in visual cortex. Aim 3 tests for normalization of activity in hippocampal circuits involved in the formation and consolidation of memory, directly testing the neural circuits involved in the memory tasks that CSPD reduction improves performance in. Age and sex dependence of these phenomena are investigated in the APP/PS1 model of AD and this study also compares to a new ApoE4-hypertension model and wild type animals with bead injections to mimic capillary stalls. Understanding the mechanism of the rapid improvement in memory function after eliminating CSPD could lead to future therapies that modulate the cognitive symptoms in AD/ADRDs.

概括 尽管许多生物标志物已在 AD/ADRD 中被发现，但最重要的影响是认知功能。 AD/ADRD 症状与脑血流缺陷或高血压等血管危险因素之间的联系 在患者中得到了广泛认可，但其机制仍在研究中。在 AD 小鼠模型中 2% 的毛细血管被停滞的中性粒细胞堵塞，这些停滞的毛细血管对 脑血流量。这种毛细血管失速灌注不足（CSPD）可能会减少氧合和营养输送 神经元，因此是 AD/ADRD 认知功能障碍的潜在驱动因素。在 AD 小鼠模型中， 工作记忆性能在数小时内得到恢复，减少毛细血管停滞的发生率以增加 使用抗中性粒细胞蛋白 Ly6G 的抗体进行脑血流分析。 CSPD 也被观察到 新的非淀粉样蛋白 ADRD 模型，用 ApoE 基因靶向替换鼠 ApoE 基因的高血压小鼠 AD 促进 ApoE4 人类等位基因。在这只小鼠中，治疗后观察到行为和流量的快速恢复 与血小板抑制剂普拉格雷一起使用，表明 CSPD 的细胞原因与 AD 中观察到的不同 模型。认知恢复的快速时间尺度对于许多病理过程来说太快了，因此排除了 血管或神经重塑。相反，记忆改善的速度表明动态变化 神经元的放电模式是救援的基础，并通过增加脑血来改善代谢支持 血流是决定神经回路功能的关键因素。这表明较慢的过程，例如 因为蛋白质的积累和重塑可能是与改善氧气和蛋白质相关的快速效应的次要因素。 血流量增加后代谢物的输送。该提案检验了脑血流恢复导致的想法 纠正血氧和氧气使用，从而导致代谢和细胞功能 神经元恢复（目标 1）。假设这种代谢变化是对异常神经的潜在纠正。 最终决定行为的活动。目标 1 将使用伽马振荡，协调神经活动 与健康的皮质功能相关，作为氧合结果的同步测量 变化。在 AD 小鼠模型中，抑制性和兴奋性神经元活性的不平衡导致 刺激的神经编码的保真度。目标 2 询问血流改善是否也可以纠正这种活动不平衡 并提高了视觉皮层中定向调节神经元的刺激编码的精度。进行 3 项测试 参与记忆形成和巩固的海马回路活动的正常化，直接 测试参与记忆任务的神经回路，减少 CSPD 可以提高记忆任务的表现。 年龄和 这些现象的性别依赖性在 AD 的 APP/PS1 模型中进行了研究，并且本研究还比较了 一种新的 ApoE4 高血压模型和通过微珠注射模拟毛细血管失速的野生型动物。 了解消除 CSPD 后记忆功能快速改善的机制可能会导致 未来调节 AD/ADRD 认知症状的疗法。