Exosomal biomarkers of brain insulin resistance associated with regional atrophy in Alzheimer's disease.
Exosomal biomarkers of brain insulin resistance associated with regional atrophy in Alzheimer's disease.
复制标题
DOI：
10.1002/hbm.23494
复制
发表时间：
2017-04
影响因子：
4.8
通讯作者：
Kapogiannis D
中科院分区：
文献类型：
--
作者：
Mullins RJ;Mustapic M;Goetzl EJ;Kapogiannis D
脑胰岛素抵抗（IR）是阿尔茨海默病（AD）的特征性疾病，其依赖于胰岛素受体底物-1（IRS-1）的磷酸化。先前，我们证明了AD患者与对照相比在神经源富集的血浆外泌体中较高的pSer 312-IRS-1（无效胰岛素信号传导）和较低的p-panTyr-IRS-1（有效胰岛素信号传导）。在这里，我们假设这些外泌体生物标志物与AD中的脑萎缩相关。我们研究了24例生物标志物支持的可能AD（低CSF Aβ42）受试者。从血浆中分离外泌体，使用L1 CAM免疫沉淀富集神经来源，并测量pSer 312-和p-panTyr-IRS-1磷酸型。通过脑组织类型分割MPPT图像，并针对pSer 312-和p-panTyr-IRS-1进行灰质的基于体素的形态测定（VBM）分析。由于IRS-1的脑表达存在区域性差异，我们使用艾伦脑图谱对VBM结果和IRS-1表达进行空间比较。脑体积与P-panTyr-IRS-1呈正相关，与pSer 312-IRS-1呈负相关，区域模式惊人相似（双侧顶枕交界处，R颞中回）。这种体积关联模式与艾伦人脑图谱正常脑IRS-1表达在空间上相关。因此，脑IR的外泌体生物标志物与AD中的萎缩相关，正如其病理生理作用所预期的那样，并且以反映区域IRS-1表达的模式这样做。此外，神经源性血浆外泌体可以从特定的大脑区域恢复分子信号。
Brain insulin resistance (IR), which depends on Insulin-Receptor-Substrate-1 (IRS-1) phosphorylation, is characteristic of Alzheimer's disease (AD). Previously, we demonstrated higher pSer312-IRS-1 (ineffective insulin signaling) and lower p-panTyr-IRS-1 (effective insulin signaling) in neural origin-enriched plasma exosomes of AD patients vs. controls. Here, we hypothesized that these exosomal biomarkers associate with brain atrophy in AD. We studied 24 subjects with biomarker-supported probable AD (low CSF Aβ42). Exosomes were isolated from plasma, enriched for neural origin using immunoprecipitation for L1CAM, and measured for pSer312- and p-panTyr-IRS-1 phosphotypes. MPRAGE images were segmented by brain tissue type and voxel-based morphometry (VBM) analysis for gray matter against pSer312- and p-panTyr-IRS-1 was conducted. Given the regionally variable brain expression of IRS-1, we used the Allen Brain Atlas to make spatial comparisons between VBM results and IRS-1 expression. Brain volume was positively associated with P-panTyr-IRS-1 and negatively associated with pSer312-IRS-1 in a strikingly similar regional pattern (bilateral parietal-occipital junction, R middle temporal gyrus). This volumetric association pattern was spatially correlated with Allen Human Brain atlas normal brain IRS-1 expression. Exosomal biomarkers of brain IR are thus associated with atrophy in AD as could be expected by their pathophysiological roles and do so in a pattern that reflects regional IRS-1 expression. Furthermore, neural-origin plasma exosomes may recover molecular signals from specific brain regions.