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Current Neurovascular Research


ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Research Article

Tandem Mass Tag (TMT) Quantitative Proteomic Analysis of Serum Exosomes in Cerebral Small-vessel Disease (CSVD) Patients With Depressive Symptoms

Author(s): Yanjing Lu, Rong Shen, Hao Zhu, Qian Feng, Yifan Li, Wenxin Xu, Dayong Zhang, Zhong Zhao* and Hua Zhou*

Volume 19, Issue 5, 2022

Published on: 18 November, 2022

Page: [449 - 461] Pages: 13

DOI: 10.2174/1567202620666221103122109

Price: $65


Background: Depressive symptoms are one of the main clinical features of the cerebral small-vessel disease (CSVD). However, the pathogenesis of depressive symptoms of CSVD has not been fully studied, and a lack of effective diagnostic methodseffective diagnostic methods exists. Recently, the emerging body of evidence regarding exosomes has rendered them potentially key players in the neuropsychiatric disease theragnostic. This study’s aim was to investigate serumexosome proteomic expression in CSVD patients with depressive symptoms and to screen and analyze potential biomarkers for clinical diagnosis.

Methods: Serum samples were collected from 36 CSVD patients, including 18 cerebral small-vessel disease (CSVD+D) patients with depressive clinical manifestations and 18 cerebral small-vessel disease patients that did not present depression-related clinical manifestations (CSVD-D). This investigation employed tandem mass tag (TMT) combined with mass spectrometry for sample detection and quantitative analysis of proteins. The differential proteins with significant dysregulated expression levels in patient plasma exosomes were screened and analyzed through bioinformatics techniques.

Results: This investigation focused on a global collection of 659 quantifiable proteins. Compared to the CSVD-D group, 7 up-regulated and 30 down-regulated proteins were identified in the CSVD+D group (P < 0.05). Gene ontology (GO) enrichment analyses revealed proteomic expression profile dysregulations within serum exosomes in patients with depression, such as desmosomes and keratins, rendering them as potential biomarkers. Kyoto encyclopedia of genes and genomes (KEGG) database investigations revealed the differentially expressed proteins to be highly aggregated within the estrogen signaling pathway.

Conclusion: This investigation pioneered TMT proteomic evaluation of serum exosomes within CSVD patients suffering from depression and reveals the shifts in proteomic expression profiles by serum exosomes within such patients. This study identified several important molecular / signal pathway abnormalities related to depression. These results provide a possible means to further clarify the pathogenesis of depressive symptoms of cerebrovascular disease and its diagnosis and treatment in the future.

Keywords: Proteomic, exosome, cerebral small-vessel disease, depression, estrogen, desmosomes, keratins.

Georgakis MK, Duering M, Wardlaw JM, Dichgans M. WMH and long-term outcomes in ischemic stroke. Neurology 2019; 92(12): e1298-308.
[] [PMID: 30770431]
van der Flier WM, Skoog I, Schneider JA, et al. Vascular cognitive impairment. Nat Rev Dis Primers 2018; 4(1): 18003.
[] [PMID: 29446769]
Brookes RL, Herbert V, Lawrence AJ, Morris RG, Markus HS. Depression in small-vessel disease relates to white matter ultrastructural damage, not disability. Neurology 2014; 83(16): 1417-23.
[] [PMID: 25230999]
Alexopoulos GS. Mechanisms and treatment of late-life depression. Transl Psychiatry 2019; 9(1): 188.
[] [PMID: 31383842]
Jeon SW, Kim YK. Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness? World J Psychiatry 2016; 6(3): 283-93.
[] [PMID: 27679767]
Torres-Platas SG, Nagy C, Wakid M, Turecki G, Mechawar N. Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides. Mol Psychiatry 2016; 21(4): 509-15.
[] [PMID: 26033239]
Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol 2015; 77(1): 13-27.
[] [PMID: 25293529]
Janas AM, Sapoń K, Janas T, Stowell MHB, Janas T. Exosomes and other extracellular vesicles in neural cells and neurodegenerative diseases. Biochim Biophys Acta Biomembr 2016; 1858(6): 1139-51.
[] [PMID: 26874206]
Tavakolizadeh J, Roshanaei K, Salmaninejad A, et al. MicroRNAs and exosomes in depression: Potential diagnostic biomarkers. J Cell Biochem 2018; 119(5): 3783-97.
[] [PMID: 29236313]
Choi JL, Kao PF, Itriago E, et al. miR-149 and miR-29c as candidates for bipolar disorder biomarkers. Am J Med Genet B Neuropsychiatric Genet 2017; 174(3): 315-23.
Nesvizhskii AI. Proteogenomics: Concepts, applications and computational strategies. Nat Methods 2014; 11(11): 1114-25.
[] [PMID: 25357241]
Delpech JC, Herron S, Botros MB, Ikezu T. Neuroimmune crosstalk through extracellular vesicles in health and disease. Trends Neurosci 2019; 42(5): 361-72.
[] [PMID: 30926143]
Zhang ZG, Buller B, Chopp M. Exosomes — beyond stem cells for restorative therapy in stroke and neurological injury. Nat Rev Neurol 2019; 15(4): 193-203.
[] [PMID: 30700824]
Gallicano GI, Bauer C, Fuchs E. Rescuing desmoplakin function in extra-embryonic ectoderm reveals the importance of this protein in embryonic heart, neuroepithelium, skin and vasculature. Development 2001; 128(6): 929-41.
[] [PMID: 11222147]
Simon R, Brylka H, Schwegler H, et al. A dual function of Bcl11b/Ctip2 in hippocampal neurogenesis. EMBO J 2012; 31(13): 2922-36.
[] [PMID: 22588081]
Wang H, Warner-Schmidt J, Varela S, Enikolopov G, Greengard P, Flajolet M. Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice. Proc Natl Acad Sci USA 2015; 112(31): 9745-50.
[] [PMID: 26195764]
Simon R, Baumann L, Fischer J, et al. Structure-function integrity of the adult hippocampus depends on the transcription factor Bcl11b/Ctip2. Genes Brain Behav 2016; 15(4): 405-19.
[] [PMID: 26915960]
De Bruyckere E, Simon R, Nestel S, et al. Stability and function of hippocampal mossy fiber synapses depend on Bcl11b/Ctip2. Front Mol Neurosci 2018; 11: 103.
[] [PMID: 29674952]
Xu W, Yao X, Zhao F, et al. Changes in hippocampal plasticity in depression and therapeutic approaches influencing these changes. Neural Plast 2020; 2020: 8861903.
[] [PMID: 33293948]
Gess B, Röhr D, Lange E, Halfter H, Young P. Desmoplakin is involved in organization of an adhesion complex in peripheral nerve regeneration after injury. Exp Neurol 2015; 264: 55-66.
[] [PMID: 25496840]
Frizell B, Dumas JA. Examining the relationship between neurosteroids, cognition, and menopause with neuroimaging methods. Curr Psychiatry Rep 2018; 20(11): 96.
[] [PMID: 30221332]
Almey A, Milner TA, Brake WG. Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females. Horm Behav 2015; 74: 125-38.
[] [PMID: 26122294]
Fan J, Li B, Ge T, et al. Berberine produces antidepressant-like effects in ovariectomized mice. Sci Rep 2017; 7(1): 1310.
[] [PMID: 28465511]
Wang G, Li Y, Lei C, et al. Quercetin exerts antidepressant and cardioprotective effects in estrogen receptor α-deficient female mice via BDNF-AKT/ERK1/2 signaling. J Steroid Biochem Mol Biol 2021; 206: 105795.
[] [PMID: 33246157]
Chhibber A, Woody SK, Karim Rumi MA, Soares MJ, Zhao L. Estrogen receptor β deficiency impairs BDNF–5-HT 2A signaling in the hippocampus of female brain: A possible mechanism for menopausal depression. Psychoneuroendocrinology 2017; 82: 107-16.
[] [PMID: 28544903]
Villa A, Vegeto E, Poletti A, Maggi A. Estrogens, neuroinflammation, and neurodegeneration. Endocr Rev 2016; 37(4): 372-402.
[] [PMID: 27196727]
Zhang Z, Qin P, Deng Y, et al. The novel estrogenic receptor GPR30 alleviates ischemic injury by inhibiting TLR4-mediated microglial inflammation. J Neuroinflammat 2018; 15(1): 206.
[] [PMID: 30001721]
Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017; 541(7638): 481-7.
[] [PMID: 28099414]
Habib P, Beyer C. Regulation of brain microglia by female gonadal steroids. J Steroid Biochem Mol Biol 2015; 146: 3-14.
[] [PMID: 24607811]
Guo H, Yang J, Liu M, et al. Selective activation of estrogen receptor β alleviates cerebral ischemia neuroinflammatory injury. Brain Res 2020; 1726: 146536.
[] [PMID: 31676226]
Choi H, Mun S, Joo EJ, Lee KY, Kang HG, Lee J. Serum proteomic analysis of major depressive disorder patients and their remission status: Novel biomarker set of zinc-alpha-2-glycoprotein and keratin type II cytoskeletal 1. Int J Biol Macromol 2021; 183: 2001-8.
[] [PMID: 34052271]
Szymanski WG, Zauber H, Erban A, Gorka M, Wu XN, Schulze WX. Cytoskeletal components define protein location to membrane microdomains. Mol Cell Proteomics 2015; 14(9): 2493-509.
[] [PMID: 26091700]
Rorke EA, Adhikary G, Young CA, et al. Structural and biochemical changes underlying a keratoderma-like phenotype in mice lacking suprabasal AP1 transcription factor function. Cell Death Dis 2015; 6(2): e1647.
[] [PMID: 25695600]
Ghebrehiwet B, Joseph K, Kao A, et al. Interaction of high-molecular-weight kininogen with endothelial cell binding proteins suPAR, gC1qR and cytokeratin 1 determined by Surface Plasmon Resonance (BiaCore). Thromb Haemost 2011; 105(6): 1053-9.
[] [PMID: 21544310]
Kang G, Zhang Y, Liu R, et al. Fibrinogen and kininogen are potential serum protein biomarkers for depressive disorder. Clin Lab 2019; 65(10/2019): 190312.
[] [PMID: 31625351]
Pillat MM, Lameu C, Trujillo CA, et al. Bradykinin promotes neuron-generating division of neural progenitor cells through ERK activation. J Cell Sci 2016; 129(18): 3437-48.
[PMID: 27528403]
Nascimento IC, Glaser T, Nery AA, Pillat MM, Pesquero JB, Ulrich H. Kinin-B1 and B2 receptor activity in proliferation and neural phenotype determination of mouse embryonic stem cells. Cytometry A 2015; 87(11): 989-1000.
[] [PMID: 26243460]
Negraes PD, Trujillo CA, Pillat MM, Teng YD, Ulrich H. Roles of kinins in the nervous system. Cell Transplant 2015; 24(4): 613-23.
[] [PMID: 25839228]
Naaldijk YM, Bittencourt MC, Sack U, Ulrich H. Kinins and microglial responses in bipolar disorder: A neuroinflammation hypothesis. Biol Chem 2016; 397(4): 283-96.
[] [PMID: 26859499]
Bakhtiarzadeh F, Nahavandi A, Goudarzi M, Shirvalilou S, Rakhshan K, Niknazar S. Axonal transport proteins and depressive like behavior, following Chronic Unpredictable Mild Stress in male rat. Physiol Behav 2018; 194: 9-14.
[] [PMID: 29698729]
Zavvari F, Nahavandi A. Fluoxetine increases hippocampal neural survival by improving axonal transport in stress-induced model of depression male rats. Physiol Behav 2020; 227: 113140.
[] [PMID: 32828030]
Kebouchi M, Hafeez Z, Le Roux Y, Dary-Mourot A, Genay M. Importance of digestive mucus and mucins for designing new functional food ingredients. Food Res Int 2020; 131: 108906.
[] [PMID: 32247482]
Rivet-Noor C, Gaultier A. The role of gut mucins in the etiology of depression. Front Behav Neurosci 2020; 14: 592388.
[] [PMID: 33250724]
Ciechanowska A, Ciapała K, Pawlik K, et al. Initiators of classical and lectin complement pathways are differently engaged after traumatic brain injury-time-dependent changes in the cortex, striatum, thalamus and hippocampus in a mouse model. Int J Mol Sci 2020; 22(1): 45.
[] [PMID: 33375205]

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