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症的理解集中在淀粉样蛋白和tau蛋白S（即ApoE）上，这是对大脑的代谢和能量底物的大量修复，神经血管，神经元的显着变化，导致记忆和认知异常。大脑萎缩。阿尔茨海默氏症患者的生长因子[NGF]基因治疗中的核是使用深脑刺激来增强记忆力[DBS]在大脑中。深情的神经血管耦合和血液流动，导致兴奋性传播，神经血管耦合耦合以及增强的底物/代谢供应，可能会改善阿尔茨海默氏病的广泛的血管变化。在不同时间的发育时间点，在A.大小的小鼠阿尔茨海斯的小鼠模型中显示出明显恶化的组织学变化（即斑块和缠结）对对照动物的变化，并以敲除后台一氧化氮合成酶（inos（inos）（inos）（inos）（iNOS）（inos）（inos）（iNOS）（inos）（iNOS）（iNOS）（iNOS）（iNOS）（iNOS）（Inos）（Inos）（Inos）（Inos）（Inos）（Inos）（Inos）（Inos）（iNOS），在不同的发育时间刺激。 ：nos2 - / - ）。