Tong Han, Petyuk Vladislav A, Sendtner Michael, Sood Ajay, Bennett David A, Capuano Ana W, Arvanitakis Zoe
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
J Alzheimers Dis. 2025 Apr;104(3):667-677. doi: 10.1177/13872877251319463. Epub 2025 Apr 4.
BackgroundBrain insulin signaling has been associated with both Alzheimer's disease (AD) pathology and cognitive decline, but the mechanisms remain unclear.ObjectiveTo examine whether AD-related cortically-expressed proteins modify the association of brain insulin signaling and cognitive decline.MethodsParticipants included 116 autopsied members of the Religious Orders Study (58 with diabetes matched to 58 without, by age at death, sex, and education) who had both postmortem brain (prefrontal cortex) insulin signaling (by ELISA and immunohistochemistry, including RAC-alpha serine/threonine-protein kinase or AKT1) and AD-related cortical protein measurements. Levels of five AD-related proteins including insulin-like growth factor-binding protein-5 (IGFBP-5) and inositol-tetrakisphosphate 1-kinase (ITPK1) were measured using quantitative proteomics. We conducted adjusted linear mixed model analyses to examine associations of insulin signaling measures and AD-related proteins with longitudinally assessed cognitive function.ResultsHigher levels of IGFBP-5 and lower levels of ITPK1 were each associated with higher levels of AKT1 phosphorylation (pTAKT1 /total AKT1). Additionally, higher levels of AKT1 phosphorylation were associated with faster decline in global cognition and most cognitive domains. IGFBP-5 partially mediated the association of AKT1 phosphorylation with the decline rate of global cognition and cognitive domains including perceptual speed and visuospatial abilities. Further, ITPK1 had an interaction with AKT1 phosphorylation on decline of global cognition and domains including episodic memory, perceptual speed, and visuospatial abilities.ConclusionsAD-related proteins IGFBP-5 and ITPK1 are each associated with insulin signaling AKT1 phosphorylation in the postmortem human brain. Moreover, IGFBP-5 mediates, while ITPK1 moderates, the association between AKT1 phosphorylation and late-life cognitive decline.
背景
脑胰岛素信号传导与阿尔茨海默病（AD）病理及认知衰退均有关联，但其机制尚不清楚。
目的
研究与AD相关的皮质表达蛋白是否会改变脑胰岛素信号传导与认知衰退之间的关联。
方法
参与者包括宗教团体研究中的116名尸检对象（58名糖尿病患者与58名非糖尿病患者，按死亡年龄、性别和教育程度匹配），他们均有死后大脑（前额叶皮质）胰岛素信号传导检测结果（通过酶联免疫吸附测定法和免疫组织化学法，包括RAC-α丝氨酸/苏氨酸蛋白激酶或AKT1）以及与AD相关的皮质蛋白测量结果。使用定量蛋白质组学方法测量了包括胰岛素样生长因子结合蛋白5（IGFBP-5）和肌醇四磷酸1激酶（ITPK1）在内的五种与AD相关的蛋白水平。我们进行了调整后的线性混合模型分析，以研究胰岛素信号传导指标和与AD相关的蛋白与纵向评估的认知功能之间的关联。
结果
IGFBP-5水平较高和ITPK1水平较低均与AKT1磷酸化水平较高相关（pTAKT1/总AKT1）。此外，较高的AKT1磷酸化水平与整体认知及大多数认知领域的更快衰退相关。IGFBP-5部分介导了AKT1磷酸化与整体认知衰退率以及包括感知速度和视觉空间能力在内的认知领域衰退率之间的关联。此外，ITPK1在整体认知衰退以及包括情景记忆、感知速度和视觉空间能力在内的领域方面与AKT1磷酸化存在相互作用。
结论
与AD相关的蛋白IGFBP-5和ITPK1均与死后人类大脑中的胰岛素信号传导AKT1磷酸化有关。此外，IGFBP-5起介导作用，而ITPK1起调节作用，二者共同作用于AKT1磷酸化与晚年认知衰退之间的关联。
