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

总结 虽然在AD/ADRD中已经确定了许多生物标志物，但最重要的影响是认知功能。 AD/ADRD症状与脑血流障碍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阻塞，这些停滞的毛细血管对 脑血流量这种毛细血管失速灌注缺陷（CSPD）可减少氧合和营养输送 因此是AD/ADRD中认知功能障碍的潜在驱动因素。在AD小鼠模型中， 工作记忆表现在数小时内获救，减少毛细血管停滞的发生率， 使用中性粒细胞蛋白Ly 6 G的抗体测定脑血流量。CSPD也被观察到在一个 新的非淀粉样蛋白ADRD模型，高血压小鼠用靶向的ApoE基因替换 AD促进ApoE 4人类等位基因。在该小鼠中，在治疗后观察到行为和流量的快速拯救 与血小板抑制剂普拉格雷，这表明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， 血管或神经重塑相反，记忆力提高的速度表明， 神经元的放电模式是拯救的基础，并通过增加脑血来改善代谢支持 流是决定神经回路功能的关键因素。这表明， 因为蛋白质积累和重塑可能是继发于与改善氧气和 血流量增加后代谢物的输送。这项提议验证了脑血流恢复导致 纠正血氧和氧的使用，然后导致代谢和细胞功能 神经元的恢复（目标1）。这种代谢变化被假设为异常神经元的校正的基础。 最终决定行为的活动。AIM 1将使用伽马振荡，协调神经活动 与健康的皮质功能相关，作为氧合结果的同时测量 变化在AD小鼠模型中，抑制性神经元和兴奋性神经元的活性不平衡导致AD小鼠神经元的活性降低。 神经刺激编码的保真度。目标2询问血液流动的改善是否也纠正了这种活动失衡 提高了视皮层定向调谐神经元对刺激编码的精度。目标3测试 海马回路的活动正常化，直接参与记忆的形成和巩固 测试参与记忆任务的神经回路，CSPD的减少提高了记忆任务的表现。年龄和 在AD的APP/PS1模型中研究了这些现象的性别依赖性， 新的ApoE 4-高血压模型和野生型动物，注射珠粒以模拟毛细血管失速。 了解消除CSPD后记忆功能快速改善的机制可能会导致 到未来的治疗，调节AD/ADRD的认知症状。

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.