Hyperexcitability in Alzheimer's Disease

摘要 研究表明，神经元过度兴奋是阿尔茨海默病的一个重要特征， 阿尔茨海默病（AD），因为它有助于记忆障碍和淀粉样蛋白水平的增加 β（Aβ）是疾病的特征。使用AD神经病理学的动物模型，我们认为， 最常见的过度兴奋形式是海马和皮层神经元中的同步尖峰 类似于癫痫发作之间的尖峰，称为发作间期尖峰（IIS）。我们的数据 表明IIS发生非常早，非常常见，但癫痫发作很罕见。因此，我们有一个 潜在的机会，以表征一种新的生物标志物，IIS，并澄清之间的关系， 过度兴奋和AD。 初步数据主要使用了一种小鼠模型，其中淀粉样蛋白前体的前体 蛋白（APP），Aβ的前体被突变以模拟一个患有家族性AD的瑞典家族， 在大脑中广泛表达。到5周龄时，即Aβ沉积前数月，我们发现IIS为 动物们在睡觉。随着年龄的增长，动物会出现频繁的IIS，而这种IIS发生在其他大脑状态下 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，但癫痫发作是罕见的。当我们检查小老鼠的大脑时， 基底前脑（BF）胆碱能神经元和齿状回颗粒细胞显示升高的迹象， 活跃，而不是在老年大脑的特征活动减退。我们建议BF 胆碱能神经元刺激颗粒细胞，这导致同步动作电位。在 支持，毒蕈碱胆碱能拮抗剂阿托品减少睡眠中的IIS，以及在体外 我们认为海马切片的测量值反映了异常的活动。我们现建议 用多种方法测试这些假设的实验，包括病毒介导的沉默， 体内胆碱能神经元。 在建议的最后一部分，我们将研究两种策略，我们的试点实验表明，可以 减少IIS，以确定认知和神经病理学是否得到改善。其中一个已经 在唐氏综合征的小鼠模型中进行了测试，这是一种AD流行的情况：母体 胆碱补充剂第二，神经营养因子受体p75（p75NTR）的减少， 已经在我们将使用的小鼠模型之一Tg2576小鼠中进行了测试，并且已经知道， 它能改善老鼠的记忆障碍。总之，本项目将解决AD的一个领域 一项难以澄清和有争议的研究：AD中的过度兴奋。我们建议 有早期迹象的过度兴奋，IIS，目前的机会，更好的机制， 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.