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

通过烟碱乙酰胆碱受体的选择性共激活恢复阿尔茨海默病的突触功能障碍和记忆丧失

基本信息

批准号：
10468170
负责人：
Seonil Kim
金额：
$ 15.2万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-06-30
项目状态：
已结题

项目摘要

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.

许多研究已提供证据表明，β-淀粉样肽(Aβ)可触发突触功能障碍和阿尔茨海默病(AD)前驱阶段海马体依赖记忆的丧失，但潜在的机制仍不确定。β可以通过与烟碱型乙酰胆碱的相互作用改变神经元信号转导受体(NAChRs)，在AD中引起突触功能障碍。事实上，nAChRs的丧失是突出的AD 病理，因此Aβ诱导的nAChR功能中断是海马突触缺陷的基础，导致阿尔茨海默病的记忆力丧失。然而，β对nAChR生理的影响是复杂的-β可以作为激动剂或受体上的拮抗剂。值得注意的是，目前大多数治疗阿尔茨海默病的处方药都抑制了全身乙酰胆碱(乙酰胆碱酯酶抑制剂)的分解，从而潜在地刺激所有类型的乙酰胆碱感受器。重要的是，由于对乙酰胆碱受体的非选择性刺激，它们的疗效不大。鉴于人类大脑中已有近30种神经元nAChRs亚型的报道。这暗示着截然不同在AD中，nAChR亚型受到不同程度的影响。在海马体中的三个主要nAChR亚型中， α7-、α4β2-和α3β4-nAChRs，我们发现Aβ选择性地共同影响α7-和α4β2-nAChR，但不培养的小鼠海马神经元中的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是足以逆转培养的海马神经元的Aβ效应。因此，总体假设是，建议的工作是选择性地共激活α7和α4β2 nAChRs逆转β诱导的突触功能障碍以及AD时的记忆丧失。然而，由于隔离，分离的神经元不能反映生物体的性质以及缺乏与其他细胞的接触。因此，拟议工作的意义是建立在以下科学前提之上的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。 β对阿尔茨海默病突触功能和记忆的影响因此，在拟议的工作中，我们将使用脑片电生理学和动物行为分析来验证我们的假设。此外，我们还将使用Tg2576 转基因小鼠，是阿尔茨海默病最具特点和应用最广泛的小鼠模型之一。在目标1中，我们将验证选择性共激活α7和α4β2-nAChRs逆转β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的选择性共激活的假设改善AD模型小鼠的学习和记忆能力。鉴于胆碱能缺乏与阿尔茨海默病相关，旨在恢复正常胆碱能功能的策略已被开发为治疗阿尔茨海默病的药物。不幸的是，到目前为止，还没有nAChR化合物显示出对AD的疾病修改特性。因此，海马区α7-和α4β2-nAChRs选择性共激活可逆转Aβ对AD的影响病理学是一个基本的新概念，它可能导致创新和新的治疗策略。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The autism-associated loss of δ-catenin functions disrupts social behavior.

DOI：
10.1073/pnas.2300773120
发表时间：
2023-05-30
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Mendez-Vazquez, Hadassah;Roach, Regan L.;Nip, Kaila;Chanda, Soham;Sathler, Matheus F.;Garver, Tyler;Danzman, Rosaline A.;Moseley, Madeleine C.;Roberts, Jessica P.;Koch, Olivia N.;Steger, Ava A.;Lee, Rahmi;Arikkath, Jyothi;Kim, Seonil
通讯作者：
Kim, Seonil

HIV and FIV glycoproteins increase cellular tau pathology via cGMP-dependent kinase II activation.

HIV 和 FIV 糖蛋白通过 cGMP 依赖性激酶 II 激活增加细胞 tau 病理学。

DOI：
10.1242/jcs.259764
发表时间：
2022
期刊：
Journal of cell science
影响因子：
4
作者：
Sathler,MatheusF;Doolittle,MichaelJ;Cockrell,JamesA;Nadalin,IndiaR;Hofmann,Franz;VandeWoude,Sue;Kim,Seonil
通讯作者：
Kim,Seonil