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.

项目概要 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% 尽管AD给社会带来了巨大的负担，但目前尚无有效的方法。 预防或治疗 AD 严重的蓝斑变性 (LC) 是 AD 的一个普遍特征。 整个前脑去甲肾上腺素 (NE) 的主要来源，调节正常大脑的许多方面 在年轻健康成年人的 LC 中发现了一种异常形式的 tau 蛋白，这使得 LC 成为第一个具有这种功能的区域。 人类大脑中类似 AD 的神经病理学研究表明，NE 可以促进免疫功能。 通过调节小胶质细胞吞噬作用介导 Aβ 的去除此外，还具有抗炎作用。 NE的作用已在许多研究中得到证实，因此，LC-NE系统是一个有前途的治疗靶点。 然而，在 AD 进展过程中长期 LC 刺激的后果仍不清楚。 项目，综合使用化学遗传学操作、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、突触可塑性和记忆力。 我们将确定长期直接 LC 刺激在多大程度上延缓记忆衰退 在目标 2 中，我们将描述长期 LC 刺激的效果。 在目标 3 中，我们将研究非均匀 LC 的作用。 该项目将提供更多关于大脑中结构特异性淀粉样蛋白和 tau 蛋白病理学的变性。 需要了解长期 LC 刺激减轻淀粉样蛋白和 tau 蛋白病理的程度，以及 在AD进展过程中拯救记忆功能这些信息可能会导致新的发展。 AD 疗法利用非侵入性和侵入性脑刺激技术直接参与 LC-NE 系统。