Fornix Stimulation Enhances Neurovascular Plasticity in Alzheimer's Mouse Model

 描述（由申请人提供）： 目前对阿尔茨海默病的理解集中在淀粉样蛋白和tau蛋白的积累，血管因子（即，APoE）、代谢和对脑的底物/能量供应的大幅减少、神经血管偶联的显著变化、导致记忆和认知异常的神经元损伤、胆碱能细胞损失和弥漫性脑萎缩。虽然大量的治疗方法正在试验中，但阿尔茨海默病的潜在基础仍然不清楚。因此，类似于帕金森病的多巴胺替代疗法，阿尔茨海默病的临床焦点是治疗症状（即，而不是根本原因。由于降低的中枢胆碱能功能在阿尔茨海默病中是突出的，因此目前的人类治疗集中于乙酰胆碱酯酶抑制以改善记忆。此外，一项初步试验显示，使用神经生长因子[NGF]基因治疗基底核，可增强阿尔茨海默氏症患者的胆碱能细胞功能和记忆丧失。另一种对症治疗方法是使用应用于穹窿的脑深部电刺激（DBS）来增强记忆力，目前正在随机试验中进行测试。然而，穹窿刺激也被注意到显示大脑中广泛的代谢变化。虽然DBS方法的重点是增强记忆，但穹窿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耦合，并改善整个大脑的代谢。我们假设穹窿DBS刺激通过海马刺激和胆碱能核的二次间隔刺激引起记忆增强，影响神经血管耦合和血流。间隔刺激将导致海马功能的弥漫性胆碱能增强，引起兴奋性传递、神经血管偶联和对大脑的底物/代谢供应增强的变化，可能改善阿尔茨海默病中注意到的广泛血管变化。我们建议在阿尔茨海默病的进行性小鼠模型中研究穹窿/中隔刺激在不同发育时间点的生理和血管效应，该模型显示出明显的恶化和代表性的组织学变化（即，斑块和缠结）[CVN-AD]，与敲除背景一氧化氮合成酶（iNOS：NOS2-/-）的对照动物相比。

 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-/-).