Hyperexcitability in Alzheimer's Disease

摘要 已有研究表明，神经元过度兴奋性是阿尔茨海默病的一个重要特征 疾病(AD)，因为它导致记忆障碍和淀粉样蛋白水平升高 β(Aβ)是这种疾病的特征。利用AD神经病理学的动物模型，我们认为 最常见的过度兴奋性形式是海马神经元和皮质神经元的同步尖峰。 这类似于癫痫发作之间的棘波，称为发作间期棘波(IIS)。我们的数据 提示IIS发生得很早，很常见，但癫痫发作很少见。因此，我们有一个 潜在的机会来表征一个新的生物标记物，IIS，并澄清 过度兴奋与阿尔茨海默病。 初步数据主要使用了小鼠模型，其中淀粉样前体的前体 Aβ的前体蛋白质(APP)被突变以模拟一个患有家族性AD的瑞典家庭，以及 在大脑中广泛表达。到了5周大的时候，也就是β沉积前几个月，我们发现IIS是 动物们正在睡觉。随着年龄的增长，这些动物会出现频繁的IIS，这也发生在其他大脑状态 除了睡眠，还有记忆障碍和斑块形成。在其他动物模型中 IIS也会发生，但癫痫发作很少见。当我们检查幼鼠的大脑时，我们发现 基底前脑胆碱能神经元和齿状回颗粒细胞出现升高的迹象 活跃性，而不是老年人大脑的特征是不活跃。我们建议BF 胆碱能神经元刺激颗粒细胞，导致同步动作电位。在……里面 支持，M胆碱能拮抗剂阿托品在睡眠中和体外都能降低IIS 在我们认为反映异常活动的海马片上的测量。我们现在提议 用多种方法验证这些假说的实验，包括病毒介导的沉默 活体内的胆碱能神经元。 在提案的最后部分，我们将研究我们的试点实验显示的两种策略 降低IIS以确定认知和神经病理是否得到改善。其中一个已经 在唐氏综合症的小鼠模型上进行了测试，这是一种AD流行的情况：母体 补充胆碱。第二，神经营养素受体p75(P75NTR)的减少，有 已经在我们将使用的鼠标型号之一Tg2576鼠标上进行了测试，并且已经知道 它可以改善小鼠的记忆损伤。总而言之，这个项目将解决AD的一个领域 难以澄清和有争议的研究：阿尔茨海默病中的过度兴奋。我们建议 有过度兴奋的早期迹象，IIS，这为更好的机械性提供了机会 理解和干预。

ABSTRACT It has been suggested that neuronal hyperexcitability is an important characteristic in Alzheimer’s disease (AD) because it contributes to the impairment in memory and increasing levels of amyloid β (Aβ) that characterize the disease. Using animal models of AD neuropathology we suggest that the most common form of hyperexcitability is a synchronized spike in hippocampus and cortical neurons that is similar to the spikes between seizures in epilepsy, called interictal spikes (IIS). Our data suggests that IIS occur very early and are very common, yet seizures are rare. Therefore we have a potential opportunity to characterize a novel biomarker, IIS, and clarify the relationship between hyperexcitability and AD. Preliminary data have primarily used a mouse model where the precursor to amyloid precursor protein (APP), the precursor to Aβ is mutated to simulate a Swedish family with familial AD, and expressed widely in the brain. By 5 weeks of age, months before Aβ deposition, we have found IIS as the animals are sleeping. With age the animals develop frequent IIS that occur in other brain states besides sleep and there are also memory impairments and plaque formation. In other animal models IIS also occur, yet seizures are rare. When examining the brains of the young mice we find that the basal forebrain (BF) cholinergic neurons and dentate gyrus granule cells show signs of elevated activity, instead of hypoactivity that characterizes the brain at older ages. We suggest that BF cholinergic neurons stimulate the granule cells and this leads to synchronized action potentials. In support, the muscarinic cholinergic antagonist atropine reduces the IIS in sleep, as well as in vitro measurements in hippocampal slices that we think reflect the abnormal activity. We now propose experiments to test these hypotheses with multiple methods including viral-mediated silencing of cholinergic neurons in vivo. In the last part of the proposal we will examine two strategies that our pilot experiments show can reduce IIS to determine if cognition and neuropathology are ameliorated. One of these has already been tested in a mouse model of Down’s syndrome, a condition where AD is prevalent: maternal choline supplementation. The second, a reduction of the neurotrophin receptor p75 (p75NTR), has been tested in one of the mouse models we will use, the Tg2576 mouse, and it is already known that it ameliorates memory impairments in the mice. In summary, this project will address an area of AD research which has been difficult to clarify and controversial: hyperexcitability in AD. We suggest that there are early signs of hyperexcitability, IIS, that present opportunities for better mechanistic understanding and intervention.