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. 2021 Sep;26(9):5140-5149.
doi: 10.1038/s41380-020-0804-7. Epub 2020 Jun 15.

Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance

Carla Nasca  1 , Josh Dobbin  2 , Benedetta Bigio  2 , Kathleen Watson  3 , Paolo de Angelis  2 , Marin Kautz  4 , Ashly Cochran  5 , Aleksander A Mathé  6 , James H Kocsis  5 , Francis S Lee  5   7 , James W Murrough  4 , Bruce S McEwen  2 , Natalie Rasgon  8   9
Affiliations

Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance

Carla Nasca et al. Mol Psychiatry. 2021 Sep.

Abstract

Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies, impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in vivo molecular mechanisms of brain IR until recently have proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared with age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM+ exosomes in subjects with MDD as compared with age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM+ exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM+ exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM+ exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.

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Figures

Figure 1.
Figure 1.. Increased number of L1CAM+ exosomes in subjects with MDD as compared to controls.
(A) Workflow for the isolation, enrichment and analysis of exosomes from human plasma. Magnetic beads were used for enrichment of L1CAM+ (brain-enriched) exosomes based on the immunoprecipitation of the L1CAM _target bound to the exosomal surface. (B) Expression array validated the accuracy of the exosome isolation and confirmed the exclusion of cellular contamination from cellular vesicles as showed by the low staining for GM130, a marker for cis-Golgi vesicles. In addition to positive (green rectangular) and negative (red rectangular) controls, the expression array detected the following known exosome markers (orange rectangular) in our set of samples: Flot-1, ICAM, Alix, CD81, CD63, EpCAM, ANXA5, TSG101. (C) Western blot analysis confirmed isolation of L1CAM+ exosomes. (D) Number of L1CAM+ exosomes from subjects in depressive episode during study participation (n=48) as compared to controls (n=23). * indicates significant comparisons with controls. Dashed bars indicate group mean. See also related Figure SI1.
Figure 2.
Figure 2.. Increased in-vivo IRS-1 protein expression in L1CAM+ exosomes in subjects with MDD as compared to age- and sex-matched controls.
(A) Mechanistic model of the proposed mechanistic framework in disorders of mood and cognition: the ‘docking protein’ insulin receptor substrate-1 (IRS-1) is critical for triggering downstream signal transduction pathways to mediate insulin functions on neuroplasticity. (B) Enzyme-linked immunosorbent assessment of protein expression of the insulin receptor substrate-1 (IRS-1), a modulator of neuroplasticity, in subjects in depressive episode during study participation (n=64) as compared to controls (n=29). See also SI Table 1 for demographic and clinical characteristics of the sample of 93 subjects. * indicates significant comparisons with controls. Dashed bars indicate group mean. (C) The increased level of IRS-1 in L1CAM+ exosomes is greater in subjects with MDD and is associated with suicidality and anhedonia (cluster in red).
Figure 3.
Figure 3.. Sex-specific differences in phosphorylation of IRS-1 in L1CAM+ exosomes of subjects with MDD.
(A) Enzyme-linked immunosorbent assessment of in-vivo levels of phosphorylation of IRS-1 (pSer-IRS-1) in L1CAM+ exosomes in subjects in depressive episode during study participation (n=64) as compared to controls (n=29). These data shows a sex-specific increase of pSer-IRS-1 in L1CAM+ exosomes with mean concentrations higher in women with MDD, but not men, as compared to sex-matched controls (Men (blue): p=0.3, HC: 35.1*10–7ng/mL ±1.7, n=15; MDD: 38.1*10–7ng/mL ±2.3, n=23. Women (pink): p=0.02, HC: 31.5*10–7ng/mL ±1.8, n=14; MDD: 37.6*10–7ng/mL ±1.8, n=40). Sex was not reported for 1 subject. (B) Increased in-vivo pSer-IRS-1 levels in women who exhibit greater severity of depressive symptoms. Regression analysis between pSer-IRS-1 concentrations and depression severity of depressive symptoms as assessed at the HDRS-21. Regression line is indicated in dark pink. * indicates significant comparisons with controls. Dashed bars indicate group mean.
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