Recovery of Synaptic Dysfunction and Memory Loss in Alzheimer's Disease by Selective Co-Activation of Nicotinic Acetylcholine Receptors

许多研究表明，β-淀粉样肽（Aβ）触发突触功能障碍， 阿尔茨海默病（AD）前驱期的海马依赖性记忆丧失，但潜在的 机制仍然不确定。Aβ可通过与烟碱乙酰胆碱相互作用改变神经元信号传导 受体（nAChR），其在AD中诱发突触功能障碍。其实，这是一个很大的损失， 因此，Aβ诱导的nAChR功能破坏是海马突触缺陷的基础，导致 AD的记忆丧失然而，Aβ对nAChR生理学的影响是复杂的- Aβ可以像激动剂一样起作用， 受体的拮抗剂。值得注意的是，目前大多数用于AD的处方药抑制一般的 分解乙酰胆碱（乙酰胆碱酯酶抑制剂），从而潜在地刺激所有类型的乙酰胆碱 受体。重要的是，由于乙酰胆碱受体的非选择性刺激， 鉴于在人脑中已经报道了近30种神经元nAChR亚型。这表明 nAChR亚型在AD中受到不同影响。在海马中的三种主要nAChR亚型中， α7-、α4β2-和α3β4-nAChRs，我们确定Aβ选择性地同时影响α7-和α4β2-nAChRs，但不影响α7-和α4β2-nAChRs。 α3β4受体，导致神经元和突触功能障碍， AD的重要特征。此外，我们还发现，α7-和α4β2-受体的选择性共激活， 足以逆转培养海马神经元中的Aβ效应。因此， 拟议的工作是选择性共激活α7和α4β2 nAChR逆转Aβ诱导的突触功能障碍 和记忆丧失然而，由于分离，分离的神经元不能反映生物体的性质 与其他细胞缺乏联系。因此，拟议工作的意义是基于科学前提 需要使用完整的神经回路进行进一步的研究，以研究nAChR亚型的选择性。 Aβ对AD中突触功能和记忆的影响在拟议的工作中，我们将因此使用大脑切片 电生理学和动物行为分析来验证我们的假设。此外，我们将使用Tg 2576 转基因小鼠，其中一个最好的特点，并广泛使用，小鼠模型的AD。在目标1中。我们将 检验α7-和α4β2-nAChR的选择性共激活逆转Aβ诱导的突触改变的假设。 可塑性在目标2中，我们将确定α7-和α4β2-nAChRs的选择性共激活 改善AD模型小鼠的学习和记忆。鉴于胆碱能缺乏与AD相关， 已经开发了旨在恢复正常胆碱能功能的策略作为AD的治疗药物。 不幸的是，到目前为止，还没有nAChR化合物表现出对AD的疾病修饰特性。因此，我们认为， 海马中α7-和α4β2-nAChR的选择性共激活可以逆转Aβ对AD的作用 病理学是一个基本的新概念，这可能导致创新和新颖的治疗策略。

Many studies have provided evidences that beta-amyloid peptide (Aβ) triggers synaptic dysfunction and loss of hippocampus-dependent memory in the prodromic stage of Alzheimer’s disease (AD), but the underlying mechanisms remain uncertain. Aβ can alter neuronal signaling through interactions with nicotinic acetylcholine receptors (nAChRs), which elicits synaptic dysfunction in AD. Indeed, the loss of nAChRs is the prominent AD pathology, thus Aβ-induced disruptions of nAChR function underlie deficits in hippocampal synapses, leading to memory loss in AD. However, the effect of Aβ on nAChR physiology is complex - Aβ can act like an agonist or an antagonist on the receptors. Significantly, most of currently prescribed drugs for AD inhibit the general breakdown of acetylcholine (acetylcholinesterase inhibitors), thus potentially stimulates all types of acetylcholine receptors. Importantly, they have only modest efficacy due to non-selective stimulation of acetylcholine receptors given that nearly 30 subtypes of neuronal nAChRs have been reported in the human brain. This suggests distinct nAChR subtypes are differentially affected in AD. Among the three major nAChR subtypes in the hippocampus, α7-, α4β2-, and α3β4-nAChRs, we identify that Aβ selectively affects α7- and α4β2-nAChRs together, but not α3β4-receptors, in cultured mouse hippocampal neurons, resulting in neuronal and synaptic dysfunction, an important characteristic in AD. Moreover, we reveal that selective co-activation of α7- and α4β2-receptors is sufficient to reverse the Aβ effects in cultured hippocampal neurons. Therefore, the overall hypothesis of the proposed work is that selective co-activation of α7 and α4β2 nAChRs reverses Aβ-induced synaptic dysfunction and memory loss in AD. However, isolated neurons do not reflect the nature of the organism due to the isolation and lack of contact with other cells. The significance of the proposed work thus is based on the scientific premise that further studies using intact neural circuits are needed in order to investigate nAChR subtype selectivity of Aβ effects on synaptic function and memory in AD. In the proposed work, we will thus use brain slice electrophysiology and animal behavioral assays to test our hypothesis. Moreover, we will use Tg2576 transgenic mice, one of the most well characterized, and widely used, mouse models of AD. In Aim 1. we will test the hypothesis that selective co-activation of α7- and α4β2-nAChRs reverses Aβ-induced altered synaptic plasticity. In Aim 2, we will determine the hypothesis that selective co-activation of α7- and α4β2-nAChRs improves learning and memory in AD model mice. Given that cholinergic deficiency is associated with AD, strategies aiming to restore normal cholinergic function have been developed as therapeutic drugs for AD. Unfortunately, no nAChR compounds have demonstrated disease-modifying properties for AD so far. Therefore, the idea that selective co-activation of α7- and α4β2-nAChRs in the hippocampus can reverse Aβ effects on AD pathology is a fundamental new concept, which may lead to innovative and novel therapeutic strategies.