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: 10554301
• 负责人: Qi Wang
• 金额: $ 47.48万
• 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/10554301
• 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; Euthanasia; Excision; Focused Ultrasound; Genetic; Genotype; Goals; High Pressure Liquid Chromatography; Hippocampus; 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; genetic manipulation; 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; segregation; 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 长期基因座共刺激对淀粉样蛋白/tau病理学，突触可塑性和 阿尔茨海默氏病进展期间的记忆 阿尔茨海默氏病（AD）是一种神经退行性疾病，占所有痴呆症的80％ 诊断。尽管伯恩伯恩在社会上不可能，但目前没有有效的方法 预防或治疗广告。层层基因座（LC）的严重变性是AD中无处不在的标志。 LC是 去甲肾上腺素（NE）的主要来源是整个前脑，并调节正常大脑的许多方面 功能。在年轻健康成年人的LC中发现了一种异常的tau形式，使LC成为第一个具有 人脑中的广告状神经病理学。先前的工作表明，NE收藏率免疫 通过调节小胶质细胞增多症的调节，介导的Aβ去除。另外，抗炎作用 在许多研究中已经证明了NE的。因此，LC-NE系统是一个有前途的治疗靶标 在广告中。但是，在AD进展过程中长期LC刺激的后果仍然未知。在这个 项目使用化学发生操作的合成，逆行Cre依赖性病毒消融， 免疫组织学和行为范式，我们将检查长期基因座层的影响 在Aβ和TAU小鼠模型中刺激淀粉样蛋白/TAU病理，突触可塑性和记忆力。在AIM 1中， 我们将确定长期直接直接LC模拟延迟内存的定义的程度 功能并改善突触可塑性。在AIM 2中，我们将表征长期LC模拟的影响 在AD进展过程中淀粉样蛋白和TAU病理学上。在AIM 3中，我们将检查不均匀LC的作用 大脑中结构特异性淀粉样蛋白和TAU病理的变性。该项目将提供很多 - 需要了解长期LC刺激减轻淀粉样蛋白和TAU病理的程度以及 在广告进展过程中挽救记忆功能。这样的信息可能会导致新的发展 利用非侵入性和侵入性脑刺激技术直接参与的AD治疗 LC-NE系统。