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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

治疗延缓阿尔茨海默病患者认知能力的逐渐下降疾病（AD）将把 AD 转变为可控制的发病率，这一目标尚未实现使用针对 β-淀粉样蛋白 (Aβ) 斑块沉积的药物取得了累积成果。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，两者均由交联的可溶物驱动 β-淀粉样肽寡聚体 - 神经元过度活跃“AD 周期” 值得注意的是，这一预测。认知功能障碍可以在不改变斑块沉积的情况下恢复，已被证实一些 AD 模型，例如通过延长内质开放时间的药物网状 (ER) 兰尼碱受体 2 型 (RyR2) 钙通道并抑制神经元多动症。传统的生物标志物无法询问患者“AD 周期”的任何一部分细胞分辨率，这是评估前驱阶段治疗效果的一个未实现的目标。我们针对这个问题提出了一种基于视网膜的新颖解决方案，视网膜是大脑中易于访问的部分。神经系统受到与 AD 患者大脑中类似的损害视网膜。在其出现之前形成可溶性淀粉样β-肽寡聚体和斑块沉积大脑，以及磷酸化 tau 蛋白和神经原纤维缠结在明显的 AD 病理学之前。认知能力明显下降，患者报告对比敏感度（CS）受损，这是一个主要风险跌倒和生存率下降的因素是由光感受器驱动的。当 AD 模型中存在稀疏斑块沉积时，我们在 AD 模型中获得了首个同类初步结果视网膜显示早期 CS 损伤，并且使用三个 OCT 测量视杆细胞过度活跃我们实验室开发了线粒体驱动的生物标志物，我们还发现了 CS。 5xFAD 雄性 C57BL6/J (B6J) 小鼠的损伤和视杆细胞过度活跃生物标志物发生得更快与 5xFAD 雄性 C57BL/6Tac (B6NTac) 小鼠相比，在 WT 雄性 B6J 小鼠中，视杆细胞表现出较低的水平。 OCT 能量特征与年龄匹配的 WT 雄性 B6NTac 小鼠相比，表明品系差异基线线粒体活性。我们建议测试两个具有三个具体目标的工作假设，首先，CS 受损。 B6J 5xFAD 小鼠中较早出现过度活跃的视杆能量特征和/或突触功能障碍其次，在 5xFAD 小鼠中，RyR2 靶向治疗会延迟。认知能力下降减轻了早期 CS 和能量生物标志物的变化以及杆状突触的下降活动和后来的空间记忆缺陷，但不会改变斑块沉积的速度。