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认识主要集中在淀粉样蛋白和tau蛋白的积累，血管因素(即APOE)促进疾病进展，新陈代谢和大脑底物/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，胆碱能细胞丢失，以及弥漫性脑萎缩。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不清楚。因此，与帕金森病的多巴胺替代疗法类似，阿尔茨海默病的临床重点一直是治疗症状(即记忆)，而不是根本原因。由于中枢胆碱能功能降低在阿尔茨海默病中非常突出，目前人类的治疗重点是抑制乙酰胆碱酯酶以改善记忆。此外，一项初步试验显示，使用神经生长因子[NGF]基因进入基底核治疗阿尔茨海默病患者，在增强胆碱能细胞功能和记忆丧失方面取得了令人鼓舞的结果。另一种有症状的方法是通过对穹隆应用脑深部刺激[DBS]来增强记忆，目前正在进行随机试验。然而，穹隆刺激也被注意到显示了大脑中广泛的代谢变化。虽然这种DBS方法的重点是增强记忆，但穹隆和间隔刺激也会诱导胆碱能刺激，这可以影响血管反应性和神经血管偶联，并改善整个大脑的新陈代谢。我们假设，穹隆DBS刺激通过刺激海马和隔区胆碱能核而引起记忆增强，影响神经血管偶联和血流。隔区刺激将导致海马体功能的胆碱能弥漫性增强，引起兴奋性传递、神经血管偶联的改变，并增加对大脑的底物/代谢供应，可能改善阿尔茨海默病中广泛存在的血管变化。我们建议在进行性阿尔茨海默病小鼠模型中研究穹隆/隔刺激在不同发展时间点的生理和血管效应，与背景一氧化氮合酶(iNOS：NOS2-/-)敲除的对照动物相比，该模型显示出明显的恶化，几个月来具有代表性的组织学变化(即斑块和缠结)[CVN-AD]。

 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-/-).