Fornix Stimulation Enhances Neurovascular Plasticity in Alzheimer's Mouse Model

穹窿刺激增强阿尔茨海默病小鼠模型的神经血管可塑性

• 批准号: 9269882
• 负责人: DENNIS Alan TURNER
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269882
• 关键词: Acetylcholinesterase; Acetylcholinesterase Inhibitors; Acute; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid Proteins; Animal Model; Animals; Apolipoprotein E; Atrophic; Basal Nucleus of Meynert; Blood Vessels; Blood flow; Brain; Caring; Cell Nucleus; Cell physiology; Cells; Chronic; Clinical; Clinical Trials; Cognitive; Control Animal; Data; Deep Brain Stimulation; Deterioration; Development; Diffuse; Disease; Disease Progression; Dopamine; Electrodes; Energy Supply; Etiology; Extravasation; Fibrinogen; Functional disorder; Health; Hippocampus (Brain); Histologic; Hour; Human; Knock-out; Lead; Long-Term Potentiation; Medial; Memory; Memory Loss; Metabolic; Metabolism; Modeling; Mus; NOS2A gene; Nerve Growth Factors; Neurofibrillary Tangles; Neurons; Nitric Oxide Synthase; Parkinson Disease; Pathology; Patients; Pattern; Physiological; Pilot Projects; Population; Positioning Attribute; Preparation; Replacement Therapy; Scheme; Stimulus; Testing; Time; Veterans; brain metabolism; cerebral atrophy; cholinergic; conventional therapy; experimental study; gene therapy; implantation; improved; in vivo; mouse model; neurovascular; neurovascular coupling; novel; presenilin-1; public health relevance; randomized trial; response; symptom treatment; tau Proteins; transmission process; vascular abnormality; vascular factor

 DESCRIPTION (provided by applicant): Current understanding of Alzheimer's disease focuses on accumulation of amyloid and tau proteins, enhanced disease progression with vascular factors (i.e., APoE), a large reduction in metabolism and substrate/energy supply to the brain, significant changes in neurovascular coupling, neuronal damage leading to memory and cognitive abnormalities, cholinergic cell loss, and diffuse brain atrophy. Though a large number of treatments are in trials, the underlying basis of Alzheimer's disease remains unclear. Thus, similar to dopamine replacement therapy for Parkinson's disease, the clinical focus for Alzheimer's disease has been to treat symptoms (i.e., memory) rather than the underlying cause. Since reduced central cholinergic function is prominent in Alzheimer's disease, current human treatment focuses on acetylcholinesterase inhibition for improved memory. Further, a preliminary trial showed encouraging results for enhancing cholinergic cell function and memory loss in Alzheimer's patients using nerve growth factor [NGF] gene therapy into nucleus basalis. Another symptomatic approach has been to enhance memory using deep brain stimulation [DBS] applied to the fornix, currently in being tested in a randomized trial. However, fornix stimulation has also been noted to show widespread metabolic changes in the brain. Though the focus of this DBS approach has been on memory enhancement, fornix and septal stimulation also induces cholinergic stimulation, which can affect blood vessel reactivity and neurovascular coupling and improve metabolism throughout the brain. We hypothesize that fornix DBS stimulation is causing both enhanced memory through hippocampal stimulation and secondary septal stimulation of cholinergic nuclei, affecting neurovascular coupling and blood flow. Septal stimulation would lead to diffuse cholinergic enhancement of hippocampal function, causing changes in excitatory transmission, neurovascular coupling and enhanced substrate/metabolic supply to the brain, likely improving the widespread vascular changes noted in Alzheimer's disease. We propose to study both physiological and vascular effects of fornix/septal stimulation at different time points of development in a progressive, mouse model of Alzheimer's disease that shows a clear deterioration with representative histological changes (i.e., plaques and tangles) over months [CVN-AD] in comparison to the control animals with knockout of the background nitric oxide synthetase (iNOS: NOS2-/-).

 描述（由申请人提供）： 当前对阿尔茨海默氏病的理解集中在淀粉样蛋白和tau蛋白的积累，通过血管因素（即APOE）增强疾病的进展，大脑的代谢和底物/能量供应大大减少，对大脑的底物/底物供应，神经血管造成的神经血管偶联，神经偶联，神经元损害，导致记忆和认知脑部的疾病症状症状，造成脑质量和疾病的疾病，疾病症状且疾病症状且疾病症状且疾病症状且疾病。尽管在试验中进行了大量治疗，但阿尔茨海默氏病的基础尚不清楚。这类似于帕金森氏病的多巴胺替代疗法，阿尔茨海默氏病的临床重点是治疗症状（即记忆）而不是根本原因。由于降低的中央胆碱能功能在阿尔茨海默氏病中显着，因此当前的人类治疗集中在乙酰胆碱酯酶抑制以改善记忆力。此外，一项初步试验显示，使用神经生长因子[NGF]基因疗法对核基础的神经生长因子[NGF]基因疗法增强胆碱能细胞功能和记忆力下降的令人鼓舞的结果。另一种有症状的方法是使用应用于Fornix的深脑刺激（DBS）来增强记忆，目前正在随机试验中进行测试。然而，也已经注意到前伤刺激显示大脑的宽度代谢变化。尽管这种DBS方法的重点一直放在记忆增强上，但前伤和间隔刺激也会引起胆碱能刺激，这会影响血管反应性和神经血管偶联并改善整个大脑的代谢。我们假设FORNIX DBS刺激通过海马刺激和胆碱能核的继发性间隔刺激既可以增强记忆力，从而影响神经血管偶联和血液流动。间隔刺激会导致海马功能的弥漫性胆碱能增强，从而导致兴奋性传播，神经血管耦合的变化，并增强对大脑的底物/代谢供应，从而改善了阿尔茨海默氏病中注意到的宽性血管变化。我们建议在阿尔茨海默氏病的渐进式小鼠模型中研究肉体/中间刺激的物理和血管效应，在与对照动物相比，在几个月内[CVN-AD]与对照动物相比，与对照动物相比，它与背景氧化酶合成的氧化氧化物（nitric nitric synepase）相比，在几个月内具有代表性的组织学变化（即plaques and Tangles），显示出明确的定义。