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Isoform-specific roles of AMPK in synaptic failure and memory deficit in Alzheimer's Disease

Isoform-specific roles of AMPK in synaptic failure and memory deficit in Alzheimer's Disease
AMPK 在阿尔茨海默病突触衰竭和记忆缺陷中的异构体特异性作用
批准号:
10202466
负责人:
Tao Ma
金额:
$52.63万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-07-15 至 2024-04-30

项目摘要

项目成果

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中文摘要
翻译
项目概要/摘要 与阿尔茨海默病(AD)相关的基本分子机制仍然是一个关键的知识缺口 这阻碍了有效治疗靶点和诊断/预后生物标志物的鉴定。当前 一项提案将通过研究与AMP激活相关的信号通路的作用来解决这一差距。 蛋白激酶(AMPK)亚型。AMPK作为中央细胞能量传感器来维持能量 体内平衡此外,AMPK是整合多种信号通路的纽带, 翻译(mRNA translation)。重要的是,无论是能量稳态的破坏,还是从头开始的损伤, 蛋白质合成与神经退行性疾病相关的认知综合征有关,包括 AD. AMPK的激酶催化亚基在脑内以α1和α2两种亚型存在,它们在突触中的作用 可塑性和记忆是未知的。我们产生了脑和亚型特异性条件AMPKα1和α2 敲除小鼠(AMPKα1 cKO和AMPKα2 cKO),并进行行为,电生理,成像, 生物化学测试以表征同种型特异性表型。根据我们的初步数据,我们的中心 假设AMPK同种型稳态的破坏代表了潜在的关键分子机制, AD相关的突触可塑性损伤和记忆缺陷。制定了三个具体目标, 测试假设。目的1:研究AMPK在海马突触可塑性中的作用 和记忆的形成。目的2是确定AMPK亚型特异性调节突触失败 和记忆障碍。目的3是阐明AMPK亚型特异性 对Tg 19959 AD小鼠模型中从头蛋白质合成和脑Aβ病理学的影响。项目 建议使用神经科学和AD中的多种最先进方法进行深入分析,包括小鼠 遗传学、突触电生理学、共聚焦成像和行为测试。此外,新的方法, 测量从头蛋白质合成结合质谱/蛋白质组学方法将应用于 揭示了AD大脑中的蛋白质的身份,这些蛋白质的合成由于异常信号传导而失调, AMPK异构体稳态的破坏。这种多学科的方法将使我们能够确定详细的 与AD发病机制中异常AMPK信号传导相关的细胞/分子机制, 深入了解AD和其他痴呆综合征的新型治疗靶点和诊断生物标志物。
英文摘要
Project Summary/Abstract The basic molecular mechanisms associated with Alzheimer’s disease (AD) remain a critical knowledge gap that prevents identification of effective therapeutic targets and diagnostic/prognostic biomarkers. The current proposal will address this gap by studying the role of signaling pathways associated with AMP-activated protein kinase (AMPK) isoforms in AD. AMPK functions as a central cellular energy sensor to maintain energy homeostasis. Moreover, AMPK is a nexus to incorporate multiple signaling pathways for de novo protein synthesis (mRNA translation). Importantly, both disruptions in energy homeostasis and impairments in de novo protein synthesis are implicated in cognitive syndromes associated with neurodegenerative diseases, including AD. The kinase catalytic subunit of AMPK exists in two isoforms in brain: α1 and α2, and their roles in synaptic plasticity and memory are unknown. We generated brain- and isoform-specific conditional AMPKα1 and α2 knockout mice (AMPKα1 cKO and AMPKα2 cKO), and performed behavioral, electrophysiology, imaging, and biochemical tests to characterize isoform-specific phenotypes. Driven by our preliminary data, our central hypothesis is that disruption of AMPK isoform homeostasis represents a key molecular mechanism underlying AD-associated impairments of synaptic plasticity and memory defects. Three specific aims are formulated to test the hypothesis. Aim 1 seeks to identify isoform-specific roles of AMPK in hippocampal synaptic plasticity and memory formation. Aim 2 is designed to determine AMPK isoform-specific regulation of synaptic failure and memory impairment in Tg19959 AD mouse model. Aim 3 is designed to elucidate AMPK isoform-specific effects on de novo protein synthesis and brain Aβ pathology in Tg19959 AD mouse model. The project proposes in-depth analyses using multiple state-of-art methods in neuroscience and AD, including mouse genetics, synaptic electrophysiology, confocal imaging, and behavioral tests. Moreover, novel methods to measure de novo protein synthesis combined with mass spectrometry/proteomics approach will be applied to reveal identities of proteins in AD brains whose synthesis is dysregulated because of abnormal signaling due to disruption of AMPK isoform homeostasis. This multidisciplinary approach will enable us to identify detailed cellular/molecular mechanisms associated with aberrant AMPK signaling in AD pathogenesis, providing insights into novel therapeutic targets and diagnostic biomarkers for AD and other dementia syndromes.
期刊论文(9)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1111/jnc.15541
发表时间: 2023-07
期刊: Journal of neurochemistry
影响因子: 4.7
作者: []
通讯作者:
DOI: 10.3233/jad-215303
发表时间: 2022
期刊: JOURNAL OF ALZHEIMERS DISEASE
影响因子: 4
作者: [Jester, Hannah M., Gosrani, Saahj P., Ding, Huiping, Zhou, Xueyan, Ko, Mei-Chuan, Ma, Tao]
通讯作者: Ma, Tao
DOI: 10.1016/j.neurobiolaging.2020.11.016
发表时间: 2021-03
期刊: Neurobiology of aging
影响因子: 4.2
作者: [Yang W, Zhou X, Ryazanov AG, Ma T]
通讯作者: Ma T
DOI: 10.1002/hipo.22795
发表时间: 2017-12
期刊: Hippocampus
影响因子: 3.5
作者: [Day SM, Yang W, Ewin S, Zhou X, Ma T]
通讯作者: Ma T
8
    Roles of the glycogen synthase kinase 3 alpha isoform in Alzheimers disease pathophysiology
    Targeting protein synthesis dysregulation in Down syndrome-associated cognitive impairment with aging
    Isoform-specific roles of AMPK in synaptic failure and memory deficit in Alzheimer's Disease
    Role of protein synthesis in Alzheimers disease-associated impairments of synaptic plasticity and memory
    海外基金