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 长期刺激蓝斑对淀粉样蛋白/tau病理、突触可塑性和 阿尔茨海默病进展过程中的记忆 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的一个普遍特征。信用证是 去甲肾上腺素(NE)对整个前脑的主要来源，并调节正常大脑的许多方面 功能。在年轻的健康成年人的LC中发现了一种tau的异常形式，使LC成为第一个 人类大脑中的AD样神经病理学。以前的工作表明，去甲肾上腺素有助于免疫- 通过调节小胶质细胞吞噬作用介导Aβ的清除。另外，消炎作用 去甲肾上腺素已在许多研究中得到证实。因此，LC-NE系统是一种很有前途的治疗靶点 在公元后。然而，在AD进展过程中长期LC刺激的后果仍不清楚。在这 该项目使用了一种合成的化学遗传操作，逆行依赖CRE的病毒消融， 免疫组织学和行为范式，我们将检查长期蓝斑的影响 对Aβ和Tau小鼠模型中淀粉样蛋白/tau病理、突触可塑性和记忆的刺激。在目标1中， 我们将确定长期直接LC刺激在多大程度上延缓记忆的恶化 功能，提高突触的可塑性。在目标2中，我们将描述长期LC刺激的效果 阿尔茨海默病进展过程中淀粉样蛋白和tau蛋白的病理变化。在目标3中，我们将研究非均匀LC的作用 脑部结构特异性淀粉样变性和tau病变。这项计划将提供更多- 需要深入了解长期LC刺激在多大程度上缓解淀粉样蛋白和tau病理以及 在AD过程中恢复记忆功能。这些信息可能会导致新的 利用无创和有创脑刺激技术直接参与治疗阿尔茨海默病 LC-NE系统。