Hyperexcitability in Alzheimer's Disease

阿尔茨海默病的过度兴奋

基本信息

批准号：
9263112
负责人：
Helen E Scharfman
金额：
$ 39.5万
依托单位：
NATHAN S. KLINE INSTITUTE FOR PSYCH RES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9263112
关键词：
Action Potentials Address Age Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Animal Model Animals Area Atropine Axon Benign Biological Markers Brain Cells Characteristics Cholinergic Antagonists Chronic Cognition Confusion Data Deposition Deterioration Disease Down Syndrome Electroencephalogram Epilepsy Event FOS Protein Family Frequencies Functional disorder Generations Hippocampus (Brain)Human Hyperactive behavior Impaired cognition Impairment In Vitro Injectable Intervention Life Measurement Medial Mediating Memory Memory Loss Memory impairment Methods Modeling Mus Muscarinic Antagonists Muscarinics Mutate Mutation NGFR Protein Nature Neocortex Neurofibrillary Tangles Neurons Pathogenesis Patients Population Protein Precursors Publishing REM Sleep Reaction Research Role Seizures Senile Plaques Sleep Slice Testing Tg2576 Transgenic Organisms Viral Work basal forebrain cholinergic neurons base choline supplementation cholinergic neuron dentate gyrus experimental study familial Alzheimer disease granule cell hyperphosphorylated tau improved in vivo memory consolidation mild cognitive impairment mouse Ts65Dn mouse model neuropathology novel novel marker novel therapeutic intervention overexpression potential biomarker protein expression response septohippocampal sleep epilepsy success

项目摘要

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.

抽象的有人认为神经过度兴奋是阿尔茨海默病的一个重要特征疾病（AD），因为它会导致记忆障碍和淀粉样蛋白水平增加 β (Aβ) 是该疾病的特征，我们使用 AD 神经病理学动物模型提出：最常见的过度兴奋形式是海马体和皮质神经元的同步尖峰这类似于癫痫发作之间的峰值，称为发作间期峰值 (IIS)。表明 IIS 发生得很早并且很常见，但癫痫发作很少见，因此我们有一个。表征新型生物标志物 IIS 的潜在机会，并阐明两者之间的关系过度兴奋和AD。初步数据主要使用小鼠模型，其中淀粉样蛋白前体的前体蛋白质 (APP)，Aβ 的前体被突变以模拟患有家族性 AD 的瑞典家庭，以及到 5 周龄时，即 Aβ 沉积前几个月，我们发现 IIS 已在大脑中广泛表达。随着年龄的增长，动物会经常出现在其他大脑状态下发生的 IIS。除了睡眠之外，其他动物模型中还存在记忆障碍和斑块形成。 IIS 也会发生，但癫痫发作很少见。当检查幼鼠的大脑时，我们发现前脑 (BF) 胆碱能神经元和基底回颗粒细胞显示出升高的迹象我们建议 BF 是大脑活动的特征，而不是老年人大脑活动不足的特征。胆碱能神经元刺激颗粒细胞，从而产生同步动作电位。支持，毒蕈碱胆碱能拮抗剂阿托品降低睡眠中的 IIS，以及体外我们认为海马切片的测量反映了异常活动。实验用多种方法检验这些假设，包括病毒介导的沉默体内胆碱能神经元。在提案的最后部分，我们将研究我们的试点实验表明可以的两种策略减少 IIS 以确定认知和神经病理学是否已得到改善。在患有唐氏综合症的小鼠模型中进行了测试，唐氏综合症是一种 AD 普遍存在的疾病：母亲第二种是补充胆碱，减少神经营养蛋白受体 p75 (p75NTR)。在我们将使用的鼠标型号之一 Tg2576 鼠标上进行了测试，众所周知总而言之，该项目将解决 AD 领域的问题。一项难以澄清且有争议的研究：AD 中的过度兴奋。有过度兴奋的早期迹象，IIS，这为更好的机制提供了机会理解和干预。