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

治疗性延缓阿尔茨海默病患者认知功能的进行性下降 疾病（AD）将把AD转化为可控制的发病率，这是一个尚未实现的目标。 使用针对β-淀粉样蛋白（Aβ）斑块沉积的药物实现。积累成果 表明认知丧失（与回路/突触功能障碍有关）和β-淀粉样蛋白（Aβ）斑块 沉积可以彼此独立地发生，两者都由交联的可溶性聚合物驱动。 淀粉样β肽寡聚体-神经元过度活跃“AD周期”。值得注意的是， 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，通过延长内质网开放时间的药物 内质网（ER）ryanodine受体2型（RyR 2）钙通道和抑制神经元 多动症。 常规的生物标志物不能询问患者中“AD周期”的任一部分， 细胞消退，这是在前驱期评价治疗效果的一个未达到的目标。在这里， 我们提出了一个新的解决方案，这个问题的基础上视网膜，一个容易接近的部分， 神经系统损伤与AD患者的大脑中发现的损伤相似。视网膜 可溶性淀粉样β肽寡聚体和斑块沉积， 大脑，以及磷酸化tau蛋白和神经元缠结。显性AD病理学之前 和认知能力下降是明显的，患者报告对比敏感度（CS）受损， 福尔斯的因素以及生存率下降。CS由光感受器驱动。 我们的第一个同类的初步结果，在AD模型时，有稀疏斑块沉积， 视网膜显示早期CS损伤，且使用三个OCT测量视杆过度活动 我们实验室开发的生物标志物。我们还发现， 5xFAD雄性C57 BL 6/J（B6 J）小鼠中损伤和视杆细胞活动过度生物标志物发生得更快 比5xFAD雄性C57 BL/6 Tac（B6 NTac）小鼠中的多。在WT雄性B6 J小鼠中，视杆细胞显示出较低的 OCT能量特征与年龄匹配的WT雄性B6 NTac小鼠相比，表明品系差异 线粒体活性的基线。 我们建议用三个具体目标来检验两个工作假设。首先，受损的CS， 过度活跃的杆能量信号和/或突触功能障碍发生在B6 J 5xFAD小鼠早期 比B6 NTac 5xFAD小鼠中的要多。其次，在5xFAD小鼠中，RyR 2靶向治疗延迟了 认知能力下降减轻了早期CS和能量生物标志物的变化， 活动，以及后来的空间记忆缺陷，但不改变斑块沉积的速率。

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.