Hippocampal proteomics defines pathways associated with memory decline and resilience in normal aging and Alzheimer's disease mouse models.
Hippocampal proteomics defines pathways associated with memory decline and resilience in normal aging and Alzheimer's disease mouse models.
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DOI：
10.1016/j.bbr.2016.06.002
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发表时间：
2017-03-30
影响因子：
2.7
通讯作者：
Kaczorowski, Catherine C.
中科院分区：
文献类型：
--
作者：
Neuner, Sarah M.;Wilmott, Lynda A.;Hoffmann, Brian R.;Mozhui, Khyobeni;Kaczorowski, Catherine C.
阿尔茨海默病（AD）是老年痴呆症中最常见的一种，目前尚无治愈方法。因此，识别AD认知能力下降的关键分子介质仍然是当务之急。由于衰老是阿尔茨海默病最重要的危险因素，本研究的目的是确定与“正常”衰老和阿尔茨海默病记忆缺陷发展相关的改变的蛋白质和途径，并确定可能导致阿尔茨海默病特异性症状的独特蛋白质和途径。我们使用情境恐惧条件反射来诊断8个月大的5XFAD和非转基因（Ntg）小鼠是否具有完整或受损的记忆，然后使用液相色谱-串联质谱（LC-MS/MS）来定量各组海马膜蛋白。随后的分析发现，在Ntg小鼠中有113种蛋白质与记忆状态（完整与受损）有关，在5XFAD小鼠中有103种蛋白质。36种蛋白质，包括一些与神经元兴奋性和突触可塑性有关的蛋白质（如GRIA1、GRM3和SYN1），在“正常”衰老和AD中都发生了改变。通路分析强调HDAC4是两种基因型中观察到的蛋白变化的调节因子，并确定REST表观遗传调控通路和Gi细胞内信号通路是ad特异性通路，参与调节记忆缺陷的发生。在不考虑认知状态的情况下，比较Ntg和AD的海马膜蛋白质组，鉴定出138种差异表达蛋白，包括确认性蛋白APOE和CLU。总的来说，我们提供了一组新的具有治疗潜力的假定靶点和途径，包括一组与正常衰老小鼠认知状态或导致AD的基因突变相关的蛋白质。
Alzheimer’s disease (AD), the most common form of dementia in the elderly, has no cure. Thus, the identification of key molecular mediators of cognitive decline in AD remains a top priority. As aging is the most significant risk factor for AD, the goal of this study was to identify altered proteins and pathways associated with the development of ‘normal’ aging and AD memory deficits, and identify unique proteins and pathways that may contribute to AD-specific symptoms. We used contextual fear conditioning to diagnose 8-month-old 5XFAD and non-transgenic (Ntg) mice as having either intact or impaired memory, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify hippocampal membrane proteins across groups. Subsequent analysis detected 113 proteins differentially expressed relative to memory status (intact vs impaired) in Ntg mice and 103 proteins in 5XFAD mice. Thirty-six proteins, including several involved in neuronal excitability and synaptic plasticity (e.g., GRIA1, GRM3, and SYN1), were altered in both ‘normal’ aging and AD. Pathway analysis highlighted HDAC4 as a regulator of observed protein changes in both genotypes and identified the REST epigenetic regulatory pathway and Gi intracellular signaling as AD-specific pathways involved in regulating the onset of memory deficits. Comparing the hippocampal membrane proteome of Ntg versus AD, regardless of cognitive status, identified 138 differentially expressed proteins, including confirmatory proteins APOE and CLU. Overall, we provide a novel list of putative targets and pathways with therapeutic potential, including a set of proteins associated with cognitive status in normal aging mice or gene mutations that cause AD.
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DOI：
10.1073/pnas.0700293104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Armbruster, Blaine N.;Li, Xiang;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
影响因子：
64.8
作者：
COBB, SR;BUHL, EH;SOMOGYI, P
通讯作者：
SOMOGYI, P
影响因子：
5.3
作者：
Chan, CS;Shigemoto, R;Surmeier, DJ
通讯作者：
Surmeier, DJ
影响因子：
25
作者：
De Jager, Philip L.;Srivastava, Gyan;Lunnon, Katie;Burgess, Jeremy;Schalkwyk, Leonard C.;Yu, Lei;Eaton, Matthew L.;Keenan, Brendan T.;Ernst, Jason;McCabe, Cristin;Tang, Anna;Raj, Towfique;Replogle, Joseph;Brodeur, Wendy;Gabriel, Stacey;Chai, High S.;Younkin, Curtis;Younkin, Steven G.;Zou, Fanggeng;Szyf, Moshe;Epstein, Charles B.;Schneider, Julie A.;Bernstein, Bradley E.;Meissner, Alex;Ertekin-Taner, Nilufer;Chibnik, Lori B.;Kellis, Manolis;Mill, Jonathan;Bennett, David A.
通讯作者：
Bennett, David A.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y