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

用于治疗实验性阿尔茨海默病后期空间记忆丧失的新型早期视网膜成像生物标志物

• 批准号: 10650636
• 负责人: BRUCE A. BERKOWITZ
• 金额: $ 113.56万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650636
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Appearance; Biological Assay; Biological Markers; Brain; Calcium Channel; Cognition; Contrast Sensitivity; Dementia; Deposition; Disease; Drug Targeting; Drug usage; Electron Transport Complex III; Endoplasmic Reticulum; Evaluation; Excision; Female; Functional disorder; Glutamates; Goals; Hippocampus; Hyperactivity; Impaired cognition; Impairment; In Situ; Individual; Laboratories; Learning; Left; Light; Link; Measures; Memory Loss; Memory impairment; Methods; Mitochondria; Morbidity - disease rate; Mus; Names; Nervous System; Neurofibrillary Tangles; Neurons; Optical Coherence Tomography; Patients; Pharmaceutical Preparations; Photoreceptors; Prediction of Response to Therapy; Proxy; Public Health; Reporting; Research; Resolution; Retina; Risk Factors; Rod; Ryanodine Receptor Calcium Release Channel; Senile Plaques; Synapses; Testing; Text; Therapeutic; Time; Treatment Efficacy; Water; Whole-Cell Recordings; Wild Type Mouse; biomarker driven; biomarker signature; crosslink; experience; falls; imaging biomarker; indexing; male; mild cognitive impairment; novel; prevent; rate of change; response; retinal imaging; spatial memory; tau-1

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.

通过治疗延迟阿尔茨海默氏症认知的逐步下降 疾病（AD）将AD转变为可管理的病态，这一目标尚未实现 使用针对β-淀粉样蛋白（Aβ）斑块沉积的药物进行累积 表明认知损失 沉积可以彼此独立，两者都由交联的可溶性驱动 淀粉样β-肽肽寡聚物 - 神经元多动症“ AD循环”。 可以在不改变斑块沉积的情况下恢复认知功能障碍 例如，几种AD模型，例如，通过延长内质开放时间的药物 网状（ER）Ryanodine受体2型（RYR2）钙通道和融资神经元 多动症。 常规生物标志物无法在患者的“ AD周期”的任一部分审问 细胞分辨率，在前驱阶段评估治疗疗效的未得到的目标。 我们根据视网膜提出了一个新的解决方案，以解决此问题，这是一个可访问的部分 神经系统的损害与AD患者大脑相似 在出现之前，开发可溶性淀粉样β-肽寡聚物和斑块沉积 大脑以及磷酸化的tau和神经费用缠结。 认知能力下降是证据，患者报告了对比敏感性受损（CS），这是主要风险 跌倒的因素以及降低存活率。 当AD模型中，我们的第一个初步结果在AD模型中产生稀疏的斑块沉积 视网膜显示了CS的早期损伤，并使用三个OCT测量了Rod多动症 线粒体驱动的生物标志物在我们的实验室中开发。 5xfad雄性C57BL6/J（B6J）小鼠的损伤和杆过度活跃生物标志物发生更快 在5xfad雄性C57BL/6TAC（B6NTAC）中，杆b6j小鼠的小鼠显示出较低的 OCT能量签名比年龄匹配的WT雄性B6NTAC小鼠的签名，表明应变差异 在基线线粒体活性中。 我们建议以三个特定目的测试两个工作假设。 较早的B6J 5XFAD小鼠发生了多动杆能量签名和/或突触功能障碍 在B6NTAC 5XFAD小鼠中，第二小鼠在5xFAD小鼠中延迟了RYR2靶向治疗 认知能力下降减轻早期CS和能量生物标志物的变化，杆突触下降 活动，后来的空间记忆缺陷，但不会改变斑块沉积速率。