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. 2017 Apr;38(4):1933-1940.
doi: 10.1002/hbm.23494. Epub 2017 Jan 20.

Exosomal biomarkers of brain insulin resistance associated with regional atrophy in Alzheimer's disease

Roger J Mullins #  1 , Maja Mustapic #  1 , Edward J Goetzl  2 , Dimitrios Kapogiannis  1
Affiliations

Exosomal biomarkers of brain insulin resistance associated with regional atrophy in Alzheimer's disease

Roger J Mullins et al. Hum Brain Mapp. 2017 Apr.

Abstract

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. Hum Brain Mapp 38:1933-1940, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: Alzheimer's disease; IRS-1; biomarker; exosomes; insulin resistance; magnetic resonance imaging.

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Figures

Figure 1
Figure 1
Voxel‐wise regression of p‐panTyr‐IRS‐1 and pSer312‐IRS‐1. Color map overlays represent brain regions where higher gray matter volume was associated with (A) higher exosomal p‐panTyr‐IRS‐1 (red) or (B) lower pSer312‐IRS‐1 (green). Color bars represent t values. Voxel threshold was set to P < 0.001 (uncorrected) with no cluster size thresholding for visualization with no cluster thresholding. Complete results are provided in Table 2. Brains are oriented in neurological space. Figure created in MRIcroGL version 1.150909.
Figure 2
Figure 2
Allen human brain atlas expression correlation with volumetrics. (A) IRS‐1 expression z‐score map (red‐high, green‐low) from the Allen Human Brain atlas site for subject H0351.2001. Color bar is a z‐statistic (image credit: Allen Institute). (B) Volume to p‐panTyrIRS‐1 correlation statistical map thresholded at an uncorrected P value of 0.001. Color bar is a T‐statistic. (C) Scatterplot of IRS‐1 log2 expression by strength of volumetric p‐panTyrIRS‐1 correlation. Regions showing significant volume increases with p‐panTyrIRS‐1 were also evident in the expected regional expression of IRS‐1.
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