Novel Early Retinal Imaging Biomarkers for Treating Later Spatial Memory Loss in Experimental Alzheimer's Disease

治疗延缓阿尔茨海默病患者认知功能进行性下降 疾病(AD)将把AD转变为可控的发病率，这是一个尚未实现的目标 使用靶向β-淀粉样蛋白(Aβ)斑块沉积的药物实现。累积结果 提示认知障碍(与回路/突触功能障碍有关)和β-淀粉样蛋白(Aβ)斑块 沉积可以相互独立地发生，两者都由一种可溶的交联物驱动 淀粉样蛋白β-多肽寡聚体-神经元过度活动“AD周期”。值得注意的是，预测 认知功能障碍可以在不改变斑块沉积的情况下恢复 几种AD模型，例如，通过延长内质开放时间的药物 网状Ryanodine受体2(RyR2)钙通道与神经元抑制 多动症。 传统的生物标记物不能询问患者“AD周期”的任何一部分。 细胞分辨率，在前驱阶段评估治疗效果的一个未达到的目标。这里, 我们提出了一种基于视网膜的新的解决方案，视网膜是 神经系统受损，与AD患者的大脑损伤相似。视网膜 在出现之前，会形成可溶性淀粉样蛋白β-肽低聚物和斑块沉积 大脑，以及磷酸化的tau和神经原纤维缠结。在公开的AD病理之前 和认知能力下降，患者报告对比敏感度(CS)受损，这是一个主要风险 跌倒的因素以及存活率的下降。CS由光感受器驱动。 我们首次在AD模型中发现稀疏斑块沉积的初步结果 视网膜显示CS的早期损害，并使用三个OCT测量视杆细胞过度活动 线粒体驱动的生物标记物是我们实验室开发的。我们还发现CS 5xFAD雄性C57BL6/J(B6J)小鼠的损伤和杆状多动生物标志物发生得更快 5×FAD雄性C57BL/6Tac(B6NTac)小鼠。在WT雄性B6J小鼠中，杆数显示出较低的 OCT能量信号比年龄匹配的WT雄性B6NTac小鼠更高，表明品系差异 在基线线粒体活动中。 我们建议测试两个具有三个特定目标的工作假说。首先，那个受损的CS， B6J 5xFAD小鼠出现过度活跃的杆状能量信号和/或突触功能障碍 与B6NTac 5xFAD小鼠相比。第二，在5xFAD小鼠中，RyR2靶向治疗延迟 认知功能下降缓解早期CS和能量生物标志物的变化，视杆突触的下降 活动，以及后来的空间记忆障碍，但不改变斑块沉积率。

Therapeutically delaying the progressive decline in cognition in patients with Alzheimer’s disease (AD) would transform AD into a manageable morbidity, a goal that has not been achieved using drugs targeted to β-amyloid (Aβ) plaque deposition. Accumulating results indicate that cognitive loss (linked to circuit / synaptic dysfunction) and β-amyloid (Aβ) plaque deposition can occur independent of each other, with both driven by a cross-linked soluble amyloid β-peptide oligomer - neuronal hyperactivity “AD cycle”. Remarkably, the prediction that cognitive dysfunction can be restored without altering plaque deposition has been confirmed in several AD models, for example, by drugs that prolong the opening time of the endoplasmic reticulum (ER) ryanodine receptor type 2 (RyR2) calcium channel and suppress neuronal hyperactivity. Conventional biomarkers are unable to interrogate either part of the “AD cycle” in patients at cellular resolution, an unmet goal for evaluating treatment efficacy at the prodromal stage. Here, we propose a novel solution to this problem based on the retina, a readily accessible part of the nervous system with damage similar to that found in the brain of patients with AD. The retina develops soluble amyloid β-peptide oligomers and plaque deposition before their appearance in the brain, as well as phosphorylated tau and neurofibrillary tangles. Before overt AD pathology and cognitive decline are evident, patients report impaired contrast sensitivity (CS), a major risk factor for falls as well as decreased survival. CS is driven by photoreceptors. Our first-in-kind preliminary results in an AD model when there is sparse plaque deposition in the retina show early impairment of CS, and rod hyperactivity measured using three OCT mitochondria-driven biomarkers developed in our laboratory. We have also discovered that CS impairment and rod hyperactivity biomarkers in 5xFAD male C57BL6/J (B6J) mice occur faster than in 5xFAD male C57BL/6Tac (B6NTac) mice. In WT male B6J mice, rods showed a lower OCT energy signature than in age-matched WT male B6NTac mice, indicating strain differences in baseline mitochondria activity. We propose to test two working hypotheses with three Specific Aims. First, that impaired CS, a hyperactive rod energy signature, and/or synaptic dysfunction occur earlier B6J 5xFAD mice than in B6NTac 5xFAD mice. Second that in 5xFAD mice, RyR2-targeted treatments that delay cognitive declines mitigate changes in early CS and energy biomarkers, declines in rod synaptic activity, and later spatial memory deficits but do not change the rate of plaque deposition.