The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease.
The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease.
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DOI：
10.1002/path.5056
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
De Felice FG
中科院分区：
文献类型：
--
作者：
Batista AF;Forny-Germano L;Clarke JR;Lyra E Silva NM;Brito-Moreira J;Boehnke SE;Winterborn A;Coe BC;Lablans A;Vital JF;Marques SA;Martinez AM;Gralle M;Holscher C;Klein WL;Houzel JC;Ferreira ST;Munoz DP;De Felice FG
阿尔茨海默病（AD）是一种破坏性的神经系统疾病，仍然缺乏有效的治疗方法，这刺激了对疾病修饰疗法的强烈追求。鉴于AD与脑胰岛素信号传导缺陷之间的联系日益被认可，我们研究了利拉鲁肽（一种上市用于治疗2型糖尿病的胰高血糖素样肽-1（GLP-1）类似物）在AD实验模型中的作用。胰岛素受体病理是AD脑的重要特征，其损害中枢胰岛素信号传导的神经保护作用。在本文中，我们发现利拉鲁肽可预防小鼠脑胰岛素受体和突触的丢失，并逆转AD相关β淀粉样蛋白寡聚体（AβOs）诱导的记忆障碍。使用海马神经元培养物，我们确定利拉鲁肽的神经保护机制涉及PKA信号通路的激活。将Aβ O输注到非人灵长类动物（NHP）的侧脑室中导致与记忆相关的脑区域中的胰岛素受体和突触显著丢失。利拉鲁肽全身性治疗NHP可提供部分保护，减少特定脑区域中AD相关胰岛素受体、突触和tau病理学。突触损伤和消除是已知的最早的病理变化之一，也是AD记忆障碍的最佳相关因素。结果阐明了利拉鲁肽的神经保护机制，并表明GLP-1受体激活可用于保护AD中的脑胰岛素受体和突触。版权所有© 2018作者.病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease‐modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon‐like peptide‐1 (GLP‐1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD‐linked amyloid‐β oligomers (AβOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AβOs into the lateral cerebral ventricle of non‐human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD‐related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP‐1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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影响因子：
--
作者：
Craft, Suzanne;Baker, Laura D.;Montine, Thomas J.;Minoshima, Satoshi;Watson, G. Stennis;Claxton, Amy;Arbuckle, Matthew;Callaghan, Maureen;Tsai, Elaine;Plymate, Stephen R.;Green, Pattie S.;Leverenz, James;Cross, Donna;Gerton, Brooke
通讯作者：
Gerton, Brooke
DOI：
10.1016/j.tem.2012.11.008
发表时间：
2013-02
期刊：
Trends in endocrinology and metabolism: TEM
影响因子：
--
作者：
Dailey MJ;Moran TH
通讯作者：
Moran TH
DOI：
10.1016/s0140-6736(17)31585-4
发表时间：
2017-10-07
期刊：
Lancet (London, England)
影响因子：
--
作者：
Athauda D;Maclagan K;Skene SS;Bajwa-Joseph M;Letchford D;Chowdhury K;Hibbert S;Budnik N;Zampedri L;Dickson J;Li Y;Aviles-Olmos I;Warner TT;Limousin P;Lees AJ;Greig NH;Tebbs S;Foltynie T
通讯作者：
Foltynie T
影响因子：
11
作者：
Bartolotti N;Bennett DA;Lazarov O
通讯作者：
Lazarov O
影响因子：
5.3
作者：
Abbott, MA;Wells, DG;Fallon, JR
通讯作者：
Fallon, JR