Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function.
Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function.
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DOI：
10.1002/ana.25826
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发表时间：
2020-09
影响因子：
11.2
通讯作者：
Arnold SE
中科院分区：
文献类型：
--
作者：
Arvanitakis Z;Wang HY;Capuano AW;Khan A;Taïb B;Anokye-Danso F;Schneider JA;Bennett DA;Ahima RS;Arnold SE
研究脑胰岛素信号分子标记与老年痴呆症（AD）和认知的关系，包括有或无糖尿病的老年人。这项临床病理研究来源于一项基于社区的队列研究——宗教秩序研究。我们研究了150人（平均死亡年龄为87岁，48%为女性）：75人患有糖尿病，75人没有糖尿病（按性别、死亡年龄和教育程度匹配）。通过酶联免疫吸附试验、免疫组织化学和体外胰岛素刺激脑组织，我们评估了死后额叶中回皮层的胰岛素信号传导。死后数据记录了AD神经病理学。基于17项神经心理学测试，临床评估记录了接近死亡的认知功能。在调整回归分析中，我们检查了脑胰岛素信号与糖尿病、AD和认知水平的关系。脑胰岛素受体底物-1 （IRS1）磷酸化（pS307IRS1/总IRS1）和丝氨酸/苏氨酸蛋白激酶（AKT）磷酸化（pT308AKT1/总AKT1）在糖尿病患者或非糖尿病患者中相似。AKT磷酸化与AD整体病理评分相关（p = 0.001）。相反，IRS1磷酸化与AD无关（p = 0.536）。没有发现胰岛素信号与总体AD评分的其他关联，包括使用体外脑胰岛素刺激方法时。在二次分析中，归一化的pT308AKT1与淀粉样蛋白负荷和tau缠结密度呈正相关，并且没有观察到脑胰岛素信号与神经病理的其他关联。此外，pT308AKT1归一化与整体认知功能水平较低相关（估计值= - 0.212，标准误差= 0.097;p = 0.031）。脑AKT磷酸化是胰岛素和其他生长因子信号传导的关键节点，与AD神经病理和认知功能下降有关。
To examine associations of molecular markers of brain insulin signaling with Alzheimer disease (AD) and cognition among older persons with or without diabetes. This clinical–pathologic study was derived from a community-based cohort study, the Religious Orders Study. We studied 150 individuals (mean age at death =87 years, 48% women): 75 with and 75 without diabetes (matched by sex on age at death and education). Using enzyme-linked immunosorbent assay, immunohistochemistry, and ex vivo stimulation of brain tissue with insulin, we assessed insulin signaling in the postmortem middle frontal gyrus cortex. Postmortem data documented AD neuropathology. Clinical evaluations documented cognitive function proximate to death, based on 17 neuropsychological tests. In adjusted regression analyses, we examined associations of brain insulin signaling with diabetes, AD, and level of cognition. Brain insulin receptor substrate-1 (IRS1) phosphorylation (pS307IRS1/total IRS1) and serine/threonine-protein kinase (AKT) phosphorylation (pT308AKT1/total AKT1) were similar in persons with or without diabetes. AKT phosphorylation was associated with the global AD pathology score (p = 0.001). In contrast, IRS1 phosphorylation was not associated with AD (p = 0.536). No other associations of insulin signaling were found with the global AD score, including when using the ex vivo brain insulin stimulation method. In secondary analyses, normalized pT308AKT1 was positively correlated with both the amyloid burden and tau tangle density, and no other associations of brain insulin signaling with neuropathology were observed. Moreover, normalized pT308AKT1 was associated with a lower level of global cognitive function (estimate = −0.212, standard error = 0.097; p = 0.031). Brain AKT phosphorylation, a critical node in the signaling of insulin and other growth factors, is associated with AD neuropathology and lower cognitive function.
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DOI：
10.1038/nrneurol.2017.185
发表时间：
2018-03
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Arnold SE;Arvanitakis Z;Macauley-Rambach SL;Koenig AM;Wang HY;Ahima RS;Craft S;Gandy S;Buettner C;Stoeckel LE;Holtzman DM;Nathan DM
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Nathan DM
DOI：
10.3233/jad-179939
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
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作者：
Bennett DA;Buchman AS;Boyle PA;Barnes LL;Wilson RS;Schneider JA
通讯作者：
Schneider JA
影响因子：
4.7
作者：
Kang, Somang;Kim, Chul-Hoon;Lee, Jong Eun
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Lee, Jong Eun
影响因子：
6.6
作者：
Capuano, Ana W.;Wilson, Robert S.;Arvanitakis, Zoe
通讯作者：
Arvanitakis, Zoe
DOI：
10.1016/j.bbadis.2016.10.006
发表时间：
2017-02-01
影响因子：
6.2
作者：
Kothari, Vishal;Luo, Yuwen;Babu, Jeganathan Ramesh
通讯作者：
Babu, Jeganathan Ramesh