The effects of long-term locus coeruleus stimulation on amyloid/tau pathology, synaptic plasticity, and memory during Alzheimer's disease progression

长期蓝斑刺激对阿尔茨海默病进展过程中淀粉样蛋白/tau蛋白病理学、突触可塑性和记忆的影响

• 批准号: 10346110
• 负责人: Qi Wang
• 金额: $ 47.61万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10346110
• 关键词: Abeta clearance; Ablation; Adult; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Animals; Antiinflammatory Effect; Behavioral; Behavioral Paradigm; Brain; Brain Stem; Brain region; Cell Nucleus; Cerebral cortex; Clinical; Clinical Research; Clinical Trials; Control Groups; Data; Deep Brain Stimulation; Dementia; Deterioration; Development; Diagnosis; Disease Progression; Dose; Excision; Focused Ultrasound; Genotype; Goals; High Pressure Liquid Chromatography; Hippocampus (Brain); Human; Immune; Impaired cognition; In Vitro; Inflammatory; Knowledge; Lesion; Long-Term Effects; Measures; Mediating; Memory; Memory impairment; Methods; Microglia; Monoamine Oxidase; Moods; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurotoxins; Norepinephrine; Outcome; Pathology; Patients; Performance; Phagocytes; Phagocytosis; Prefrontal Cortex; Prosencephalon; Regulation; Role; Senile Plaques; Slice; Societies; Source; Structure; Symptoms; Synaptic plasticity; System; Tauopathies; Technology; Testing; Thalamic structure; Therapeutic; Time; Vagus nerve structure; Viral; Viral Vector; Work; cognitive function; cognitive task; electric field; experimental study; hTau Mice; improved; inhibitor; insight; knowledge base; locus ceruleus structure; mouse model; neural stimulation; neuropathology; noradrenaline transporter; noradrenergic; norepinephrine system; novel; novel therapeutics; offspring; overexpression; prevent; reuptake; targeted treatment; tau Proteins; therapeutic target; translational impact; vagus nerve stimulation

Project Summary The effects of long-term locus coeruleus stimulation on amyloid/tau pathology, synaptic plasticity, and memory during Alzheimer’s disease progression Alzheimer’s disease (AD) is a neurodegenerative disease and accounts for up to 80% of all dementia diagnoses. Despite the immense burden that AD imposes on society, there is currently no effective method to prevent or treat AD. Severe degeneration of the locus coeruleus (LC) is a ubiquitous hallmark in AD. The LC is the primary source of norepinephrine (NE) to the whole forebrain and regulates many aspects of normal brain function. An aberrant form of tau is found in the LC in young healthy adults, making the LC the first region with AD-like neuropathology in the human brain. Previous work has suggested that NE facilitates the immune- mediated removal of Aβ through regulation of microglial phagocytosis. In addition, the anti-inflammatory effect of NE has been demonstrated in many studies. Therefore, the LC-NE system is a promising therapeutic target in AD. However, the consequences of long-term LC stimulation during AD progression remain unknown. In this project, using a synthesis of chemogenetic manipulation, retrograde Cre-dependent viral ablation, immunohistology, and behavioral paradigms, we will examine the effects of long-term locus coeruleus stimulation on amyloid/tau pathology, synaptic plasticity, and memory in Aβ and tau mouse models. In Aim 1, we will determine the extent to which long term direct LC stimulation delays the deterioration of memory function and improves synaptic plasticity. In Aim 2, we will characterize the effects of long-term LC stimulation on amyloid and tau pathology during AD progression. In Aim 3, we will examine the role of non-uniform LC degeneration in structure-specific amyloid and tau pathology in the brain. This project will provide much- needed insight about the extent to which long term LC stimulation mitigates amyloid and tau pathology and rescues memory functions during AD progress. Such information will likely lead to the development of new therapeutics for AD that utilize both non-invasive and invasive brain stimulation technologies to directly engage the LC-NE system.

项目摘要 长期蓝斑刺激对淀粉样蛋白/tau蛋白病理学、突触可塑性和 阿尔茨海默病进展期间的记忆 阿尔茨海默病（AD）是一种神经退行性疾病，占所有痴呆症的80 诊断。尽管AD给社会带来了巨大的负担，但目前还没有有效的方法来 预防或治疗AD。蓝斑（LC）的严重变性是AD中普遍存在的标志。述LC 去甲肾上腺素（NE）的主要来源，整个前脑和调节正常大脑的许多方面 功能在年轻健康成人的LC中发现了异常形式的tau，使LC成为第一个具有tau的区域。 人类大脑中的AD样神经病理学。以前的工作表明NE促进免疫- 通过调节小胶质细胞吞噬作用介导Aβ清除。此外，抗炎作用 在许多研究中已经证明了NE的存在。因此，LC-NE系统是一个很有前途的治疗靶点 在AD中。然而，AD进展期间长期LC刺激的后果仍然未知。在这 项目，使用化学遗传学操作的合成，逆行Cre依赖性病毒消融， 免疫组织学和行为模式，我们将研究长期蓝斑的影响， 刺激Aβ和tau小鼠模型中的淀粉样蛋白/tau病理学、突触可塑性和记忆。在目标1中， 我们将确定长期直接LC刺激延缓记忆衰退的程度 功能和改善突触可塑性。在目标2中，我们将描述长期LC刺激的影响。 淀粉样蛋白和tau蛋白病理学的影响。在目标3中，我们将研究非均匀LC的作用 脑中结构特异性淀粉样蛋白和tau病理学的变性。该项目将提供许多- 需要了解长期LC刺激减轻淀粉样蛋白和tau病理的程度， 在AD进程中挽救记忆功能。这些信息可能会导致新的发展。 AD的治疗方法，其利用非侵入性和侵入性脑刺激技术直接参与 LC-NE系统