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

摘要 虽然在AD/ADRD中发现了许多生物标志物，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 在患者中得到了很好的认可，但其机制仍在调查中。在AD的小鼠模型中， 2%的毛细血管被滞留的中性粒细胞堵塞，这些停滞的毛细血管对 脑部血流量。这种毛细血管失速灌注缺陷(CSPD)会减少氧合和营养物质的输送。 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， 工作记忆能力在几小时内被挽救，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的抗体进行脑血流检测。CSPD也在一项 新的非淀粉样ADRD模型，靶向替换小鼠载脂蛋白E基因的高血压小鼠 广告促进载脂蛋白E4人类等位基因。在这只小鼠中，观察到治疗后行为和流量的快速恢复 使用血小板抑制剂普拉格雷，提示CSPD的细胞原因与AD不同 模特们。认知恢复的快速时间尺度对于许多病理过程来说太快了，并排除了 血管或神经重塑。相反，内存改善的速度表明，动态变化 神经元的放电模式是抢救的基础，并通过增加脑血液来改善代谢支持 流量是决定神经回路功能的关键因素。这表明，较慢的进程，如 因为蛋白质的堆积和重塑可能是与改善氧气和 血流量增加后代谢物输送增加。这项提议检验了这样一个观点，即脑血流恢复导致 到血液氧合和氧气使用的校正，然后导致新陈代谢和细胞功能 神经元的恢复(目标1)。这样的新陈代谢变化被认为是对异常神经的不充分纠正 最终决定行为的活动。目标1将使用伽马振荡，协调的神经活动 与健康的皮质功能有关，作为氧合后果的同时测量 改变。在AD小鼠模型中，抑制性和兴奋性神经元活性的不平衡会导致 神经刺激编码的保真度。目标2问血流的改善是否也纠正了这种活动失衡 提高了视皮层方位调谐神经元的刺激编码精度。AIM 3测试 直接参与记忆形成和巩固的海马神经元活动的正常化 测试记忆任务中涉及的神经电路，减少CSPD可以提高性能。年龄和 在AD的APP/PS1模型中对这些现象的性别依赖性进行了研究，本研究还比较了 到一种新的载脂蛋白E4高血压模型和野生型动物，通过注射珠子来模拟毛细血管停顿。 了解消除CSPD后记忆功能快速改善的机制可能会导致 到未来调整AD/ADRD认知症状的治疗方法。

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.