Collapsin-response Mediator Protein 2 as a Marker of Adaptation and Disadaptation in Humans: Study on Depression Patients and Centenarians

Collapsin-response Mediator Protein 2 as a Marker of Adaptation and Disadaptation in Humans: Study on Depression Patients and Centenarians | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Collapsin-response Mediator Protein 2 as a Marker of Adaptation and Disadaptation in Humans: Study on Depression Patients and Centenarians Arif A. Mekhtiev, Lamiya F. Hasanova This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7507990/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background. The article concerns the study of the levels of natural autoantibody to collapsin-response mediator protein 2 (CRMP2) in the serum of the minor and major depression patients, old healthy persons and centenarians. Methods. The purified CRMP2 was used as antigen and obtained serum samples were used as the primary antibody in an indirect ELISA test. Results. The results revealed insignificant increase of the autoantibody levels in the serum of the minor depression patients and drastic, 50%-decline of their levels in the serum of the major depression patients ( p < 0.01 on Student’s t-criterion) relative to the middle-aged healthy persons. While comparing the values of natural anti-CRMP2 autoantibody in the serum of the middle-aged healthy persons, old healthy persons (78-89 years old) and centenarians (beyond 90 years old), we revealed the following regularity. Relative to the middle-aged healthy persons, the levels of anti-CRMP2 autoantibody in the serum of old healthy patients declined prominently ( p < 0.001 on Friedman’s χ 2 -criterion). However, the values of anti-CRMP2 autoantibody in the serum of the centenarians increased drastically (by 2.3 times) relative to the values of the old healthy persons used as a control group ( p < 0.001 on Friedman’s χ 2 -criterion). Conclusion. The conclusion concerning reliability of evaluation of the levels of natural anti-CRMP2 autoantibody in the serum of the humans as an adaptation marker and consideration of the molecular mechanisms of major depression as the underlying mechanisms of pre-term aging is made. natural autoantibody to collapsin-response mediator protein 2 (CRMP2) serum minor and major depression patients old healthy persons centenarians Figures Figure 1 Figure 2 Introduction The problem of evaluation techniques of humans’ adaptation degree to changing environmental and social conditions is still left as one of opaque cornerstones of modern neurobiology and health protection sciences. Though the numerous theories concerning pathogenetic mechanisms of development of worldwide-spread neurological and psychiatric diseases exist, the basic triggering mechanism of their initiation, apparently, is closely related to organism’s adaptation impairment. However, nowadays there are no available approaches or techniques capable of measuring a degree of the adaptation disturbances or, terming more exactly, a degree of disadaptation in the humans. As adaptation mechanisms are related directly to the activities of the certain brain structures, the evaluation techniques should be addressed to revealing deviations of these structures’ activities from the physiological baseline. As different researchers showed, the activities of the human major brain regions might be evaluated through analysis of blood components. Specifically, the levels of serotonin, the activities of serotonin-synthesizing enzymes and the ligand-binding indices of serotonin receptors in the human platelets reflect exactly the values of all these indices in the human brain cortex ( 1 , 2 ). Furthermore, the levels of natural autoantibody directed to all human tissue proteins, including subcellular nuclear proteins, realize actually protein homeostasis functions and reflect their levels in all the organism’s tissues ( 3 , 4 ) and in the brain subcortical structures (5). Hence, measuring the levels of a certain protein in the human platelets and the levels of natural autoantibody to a certain protein in the human serum give grounds to evaluate this protein’s levels in the brain cortex and subcortical structures, correspondently. Hence, basing on these data and taking into account the direct engagement of the brain subcortical structures to an organism’s adaptation to natural and social environment, the goal of the present study was measuring the level of natural autoantibody to serotonin-modulated collapsin-response mediator protein 2 (CRMP2) ( 6 ) in the serum of depression patients, old healthy persons and centenarians. Methods and Materials The studies were carried out on 20 patients diagnosed with major depression, 10 patients diagnosed with minor depression, 10 middle-aged healthy persons (up to 41years old) as a control group, 15 old healthy persons (78–89 years old) and 17 centenarians (above 90 years old). Patients’ depression degrees were measured basing on their evaluation on the Zung Anxiety Rating Scale ( 7 ) and Hamilton Rating Scale for Anxiety ( 8 ). The blood samples were taken from the all studied persons basing on their written consent in the Omur Clinics and Gerontological Center of Baku city. The blood samples were taken from the all studied persons into the sample tubes containing 5% EDTA as anticoagulant at a ratio (v/v) 1:5 to the blood. The plasma of all blood samples was centrifuged at 9000 rcf during 15 min and a supernatant as a serum was saved. The levels of natural anti-CRMP2 autoantibody in the serum were evaluated through application of indirect ELISA test on the polysterene plates with moderate level of adsorption (Sigma, Germany) ( 9 ). The purified CRMP2 was used as an antigen at a concentration of 20 µg/mL in 0.1 M tris-HCl buffer (pH 8.6). 24 h later since addition of CRMP2 into the wells of the polysterene plate, they were washed four times and the serum samples used as a primary antibody at a dilution rate 1:50 (v/v) in the antibody buffer (0.04 M phosphate buffer (pH 7.3), 015 M NaCl, 0.5 mg/mL of Tween-20 and 1 mg/mL of bovine serum albumin), were added to the wells. 24 h later the wells were washed and the anti-human murine antibody with conjugated horseradish peroxidase used as a secondary antibody at a dilution rate 1:1000 (v/v) in the antibody buffer was added to the wells. 3 h later the wells were washed and peroxidase enzyme substrate – orthophenylendiamine in 0.05 M phosphate-citrate buffer (pH 4.5) at a concentration of 0.5 mg/mL was added. The plate was placed into a dark compartment and 30 min later the reaction was stopped by adding 50 µL of 3 M NaOH into each well. The results of the reaction were recorded in the photometer for ELISA test “Molecular Devices Spectra Max 250” (MTX Lab Systems, Inc., USA) at wavelength 492 nm (wavelength of comparison 630 nm). The obtained experimental data were analyzed with application of Student’s t-criterion and Friedman’s χ 2 -criterion. Results The depression degrees in the studied patients were evaluated through the Zung Anxiety Rating Scale ( 7 ) and Hamilton Anxiety Rating Scale ( 8 ) and the patients with minor and major depression degrees were diagnosed. Relative to the middle-aged healthy persons the levels of natural anti-CRMP2 autoantibody in the serum of the minor depression patients increased insignificantly: 0.038 ± 0.005 vs. 0.045 ± 0.005 optical units of extinction (OUE, p > 0.05). At the same time, drastic, 50%-decline of the levels of natural anti-CRMP2 autoantibody in the serum of the major depression patients relative to the middle-aged healthy persons was observed (0.019 ± 0.002 vs. 0.038 ± 0.005 OUE, p < 0.01 on Student’s t-criterion, Fig. 1 ). While comparing the values of natural anti-CRMP2 autoantibody in the serum of the middle-aged healthy persons, old healthy persons (78–89 years old) and centenarians (beyond 90 years old), we revealed the very interesting regularity. Relative to the middle-aged healthy persons, the levels of natural anti-CRMP2 autoantibody in the serum of old healthy patients declined prominently (0.038 ± 0.005 vs. 0.023 ± 0.001 OUE, p < 0.001 on Friedman’s χ 2 -criterion, Fig. 2 ). However, the values of natural anti-CRMP2 autoantibody in the serum of the centenarians increased drastically (by 2.3 times) relative to the values of the old healthy persons used in this case as a control group due to their age proximity to the centenarians’ ages: 0.054 ± 0.006 vs. 0.023 ± 0.001 OUE ( p < 0.001 on Friedman’s χ 2 -criterion, Fig. 2 ). On a whole, the results indicate to insignificant increase of the levels of natural anti-CRMP2 autoantibody in the serum of the minor depression patients and drastic, 50%-decline of their levels in serum of the major depression patients relative to the middle-aged healthy persons. Considering the changes of the levels of natural anti-CRMP2 autoantibody in the serum of persons in relation to aging, prominent decline of their levels in the old healthy persons relative to the middle-aged healthy persons was noted. Conversely, drastic increase of the levels of natural anti-CRMP2 autoantibody in the serum of centenarians relative to the old healthy persons was observed. Discussion The results obtained in this study demonstrate insignificant increase of natural anti-CRMP2 autoantibody levels in the serum of the minor depression patients, whereas 50%-decline of their levels in the serum of the major depression patients relatively to the middle-aged healthy persons was observed. As our earlier studies carried out on the animal depression model showed, the levels of natural anti-CRMP2 autoantibody in the serum reflect CRMP2 levels in the brain subcortical structures (5). Hence, the revealed dynamics of these autoantibody levels indicates indirectly to induction of low-degree adaptation in the brain subcortical structures of the minor depression patients and to manifestation of prominent disadaptation in these structures of the major depression patients. Such conclusion concerning the direct relationship of upregulation of the levels of natural anti-CRMP2 autoantibody in the serum with organism’s adaptation to stressful conditions is made basing on the results of our other earlier studies. In particular, in the serum taken from the patients at the day of an appointed abdominal surgery, the levels of natural anti-CRMP2 autoantibody increased drastically relatively to their levels in the serum of healthy volunteers of the same age (9). Furthermore, in the brains of the originally fresh-water fishes (the semi-migratory fishes Caspian roach ( Rutilus rutilus caspicus ) and carpbream ( Abramis brama orientalis ) and the migratory fish – shemaya ( Chalcalburnus chalcoides )) dwelling permanently in brackish water (containing 12‰ NaCl) the levels of serotonin-modulating anticonsolidation protein (SMAP) which included CRMP2 as a constituent protein, increased sharply relative to the fishes of the same species dwelling permanently in the familiar fresh water conditions (10), as well as in the brains of the originally fresh-water common carp ( Cyprinus carpio L. ) under the effects of brackish water in the model experiments. In the hypothalamus and epiphysis of the Wistar male rats exposed to 14-day uninterrupted light desynchronization, upregulation of CRMP2 was observed (11). In that research two times intranasal CRMP2 administration to the animals of the experimental group with one-week interval brought to a significant decrease of their anxiety behavioral indices in the elevated plus-maze and sharp downregulation of the stress-related hormone cortisol levels in their serum. Hence, all the studies listed above support the idea of upregulation of the levels of CRMP2 in the brain and of natural anti-CRMP2 autoantibody in the serum as a marker of positive adaptation to adverse environmental and intrinsic (psychological) stressful conditions. Consequently, downregulation of the levels of natural anti-CRMP2 autoantibody in the serum of the major depression patients, conversely, might be considered as a marker of poor adaptation or rather disadaptation to stressful conditions experienced by the patients. The observed downregulation of the levels of natural anti-CRMP2 autoantibody in the serum of the old-healthy persons relative to the middle-aged healthy persons is, apparently, due to aging-related decline of serotonergic system activity in the human brains and supports the results of other researchers concerning the fading dynamics of serotonergic system in the brains of humans with aging. In particular, serotonin receptors’ density is higher at birth than in the adult brain (12). Furthermore, several post mortem studies on the human brains reported a reduction in the number of cortical 5-HT1A, 5-HT1B/D, and 5-HT2A receptors’ binding sites with aging in frontal lobe, occipital lobe, and hippocampus (13, 14, 15, 16, 17, 18, 19). In addition, the age-related decline in the cortical 5-HT2A binding in alive persons and PET imaging with [11C]N-methylspiperone, an affinity ligand for 5-HT2A, were as well shown (20, 21). Such reduction of the levels of natural anti-CRMP2 autoantibody in the serum of the old-healthy persons, reflecting correspondently the CRMP2 levels in their brain subcortical structures, might be a marker of age-related organism’s senescence and outcoming disadaptation manifestations. Considering on one line the approximately similar values of the levels of natural anti-CRMP2 autoantibody in the serums of the major depression patients and of the old-healthy persons that undergo the natural senescence process with accompanying fading dynamics of the serotonergic system activity in their brain subcortical structures, the conclusion concerning the basic decline of serotonergic system activity in those structures of the major depression patients as a pre-term, accelerated aging following disadaptation process to social environmental conditions might be done. The unexpected, as it may appear to a first glance, sharp upregulation of the levels of natural anti-CRMP2 autoantibody in the serum of the centenarians relative to the old-healthy persons as an age-adequate control group, apparently, indicates to the correspondent upregulation of CRMP2 in the centenarians’ brain subcortical structures. This result gives valid grounds to making a conclusion concerning a formation of high adaptation potential in the members of this age group. Such conclusion is, actually, supported by other researchers of a big cohort of centenarians, who demonstrated two times less incidence of depression manifestations relative to the octogenarians, comprising 81-90-age-old life interval (22), and this way proved the existence of their higher level of adaptation to the social conditions and the higher level of optimistic mood in comparison to the octogenarians. Declarations Ethics declaration. All tests on humans were carried out in agreement with the existing International Ethical Principles. Written consent was obtained from all participants of the above tests. The ethical approval was obtained from the Ethics Committee of the Academician Abdulla Garayev Institute of Physiology. Disclosure of potential conflicts of interest. The authors state of absence of any potential conflict of interests. Funding source. There was no funding source in conducting the described studies. References Collins CM, Kloek J, Elliott JM. (2013): Parallel changes in serotonin levels in brain and blood following acute administration of MDMA. J Psychopharmacol 27: 109–112. DOI: 10.1177/0269881112463123 Elliott JM, Kent A. (1989): Comparison of [125I]iodolysergic acid diethylamide binding in human frontal cortex and platelet tissue. J Neurochem 53: 191–196. DOI: 10.1111/j.1471-4159 Lacroix-Desmazes S, Kaveri SV, Mouthon L, Ayouba A, Malachere E, Coutinho A, Kazaychkine MD. (1998): Self-reactive natural autoantibodies in healthy individuals. J Immunology Methods 216:117-137. Mekhtiev AA, Ismailova US. (2021): Central serotonergıc trophıc support of retına and ıts ımpaırment ın retınıtıs pıgmentosa on anımal model and clınıcs. J Neurophysiology 52: 30-38. Hasanova LF. (2022): The changes of serotonin-modulating anticonsolidation protein and dihydropyrimidinase-related protein 2 in the amygdala and blood of depressive rats. Azerbaijan J Physiol 37: 7–12. DOI: 10.59883/ajp.37 Inagaki N, Chihara K, Arimura N, Ménager C, Kawano MN, et al. (2001): CRMP-2 induces axons in cultured hippocampal neurons. Nature Neuroscience 4:781–782. Dunstan DA, Scott N. (2020): Norms for Zung's Self-rating Anxiety Scale. BMC Psychiatry 20:90. doi: 10.1186/s12888-019-2427-6. Thompson E. (2015): Hamilton Rating Scale for Anxiety (HAM-A). Occupational Medicine 65: 601. DOI: 10.1093/occmed/kqv054 Guliyeva ShM, Mekhtiev AA. (2023): Engagement of dihydropyrimidinase-related protein 2 in regulation of anxiety in humans. I.M.Sechenov Russian Journal Physiol 108:34-45. Mustafayev NJ, Mekhtiev AA. (2013): Adaptive increase of serotonergic system activity in tissues of half-migratory and migratory fish at increased water salinity. J Evol Biochem Physiol 49: 443-448. Zulfugarova P, Mekhtiev AA. (2024): Central and hormonal mechanisms of adaptation to desynchronization stress. Integrative Physiology 5(2):34-41. Azmitia EC, Whitaker-Azmitia PM. (1991): Awakening the sleeping giant: Anatomy and plasticity of the brain serotonergic system. J Clin Psychiatry 52: 4–16. Arranz B, Eriksson A, Mellerup E, Plenge P, Marcusson J. (1993): Effect of aging in human cortical pre- and postsynaptic serotonin binding sites. Brain Res 620: 163–166. Cheetham S, Crompton M, Katona C, Horton R. (1988): Brain 5-HT2 receptor binding sites in depressed suicide victims. Brain Res 443: 272–280. Gross-Isseroff R, Salama D, Isreli M, Biegon A. (1990): Autoradiographic analysis of [3H]ketansterin binding in the human brain postmortem: effect of suicide. Brain Res 507: 208–215. Marcusson J, Morgan D, Winblad B, Finch C. (1984): Serotonin-2 binding sites in human frontal cortex and hippocampus. Selective loss of S-2A sites with age. Brain Res 311: 51–56. Marcusson J, Oreland L, Winblad B. (1984): Effect of age on human brain serotonin (S-1) binding sites. J Neurochem 43: 1699–1705. Shih J, Young H. (1978): The alteration of serotonin binding sites in aged human brained. Life Sci 23: 1441–1448. Sparks D. (1989): Aging and Alzheimer's disease. Altered cortical serotonergic binding. Arch Neurol 46: 138–140. Iyo M, Yamasaki T. (1993): The detection of age-related decrease of dopamine D1, D2 and serotonin 5-HT2 receptors in living human brain. Prog Neuro-Psychopharmacol Biol Psychiatry 17: 415–421. Wong D, Wagner HJ, Dannals R, Links J, Frost J, Ravert H, et al. (1984): Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain. Science 226: 1393–1396. Margrett J, Martin P, Woodard JL, Miller LS, MacDonald M, Baenziger J, et al. (2010): Depression among centenarians and the oldest old: contributions of cognition and personality. Gerontology 56: 93-9. DOI: 10.1159/000272018. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 01 Dec, 2025 Reviews received at journal 01 Dec, 2025 Reviews received at journal 27 Nov, 2025 Reviewers agreed at journal 21 Nov, 2025 Reviewers agreed at journal 21 Nov, 2025 Reviewers invited by journal 06 Sep, 2025 Editor assigned by journal 06 Sep, 2025 Submission checks completed at journal 06 Sep, 2025 First submitted to journal 01 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7507990","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":512571947,"identity":"c9062325-4643-4a82-a7ed-10c84e7b11b8","order_by":0,"name":"Arif A. 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Though the numerous theories concerning pathogenetic mechanisms of development of worldwide-spread neurological and psychiatric diseases exist, the basic triggering mechanism of their initiation, apparently, is closely related to organism\u0026rsquo;s adaptation impairment. However, nowadays there are no available approaches or techniques capable of measuring a degree of the adaptation disturbances or, terming more exactly, a degree of disadaptation in the humans. As adaptation mechanisms are related directly to the activities of the certain brain structures, the evaluation techniques should be addressed to revealing deviations of these structures\u0026rsquo; activities from the physiological baseline. As different researchers showed, the activities of the human major brain regions might be evaluated through analysis of blood components. Specifically, the levels of serotonin, the activities of serotonin-synthesizing enzymes and the ligand-binding indices of serotonin receptors in the human platelets reflect exactly the values of all these indices in the human brain cortex (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Furthermore, the levels of natural autoantibody directed to all human tissue proteins, including subcellular nuclear proteins, realize actually protein homeostasis functions and reflect their levels in all the organism\u0026rsquo;s tissues (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) and in the brain subcortical structures (5). Hence, measuring the levels of a certain protein in the human platelets and the levels of natural autoantibody to a certain protein in the human serum give grounds to evaluate this protein\u0026rsquo;s levels in the brain cortex and subcortical structures, correspondently. Hence, basing on these data and taking into account the direct engagement of the brain subcortical structures to an organism\u0026rsquo;s adaptation to natural and social environment, the goal of the present study was measuring the level of natural autoantibody to serotonin-modulated collapsin-response mediator protein 2 (CRMP2) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) in the serum of depression patients, old healthy persons and centenarians.\u003c/p\u003e"},{"header":"Methods and Materials","content":"\u003cp\u003eThe studies were carried out on 20 patients diagnosed with major depression, 10 patients diagnosed with minor depression, 10 middle-aged healthy persons (up to 41years old) as a control group, 15 old healthy persons (78\u0026ndash;89 years old) and 17 centenarians (above 90 years old). Patients\u0026rsquo; depression degrees were measured basing on their evaluation on the Zung Anxiety Rating Scale (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) and Hamilton Rating Scale for Anxiety (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e The blood samples were taken from the all studied persons basing on their written consent in the Omur Clinics and Gerontological Center of Baku city.\u003c/p\u003e\u003cp\u003eThe blood samples were taken from the all studied persons into the sample tubes containing 5% EDTA as anticoagulant at a ratio (v/v) 1:5 to the blood. The plasma of all blood samples was centrifuged at 9000 rcf during 15 min and a supernatant as a serum was saved. The levels of natural anti-CRMP2 autoantibody in the serum were evaluated through application of indirect ELISA test on the polysterene plates with moderate level of adsorption (Sigma, Germany) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The purified CRMP2 was used as an antigen at a concentration of 20 \u0026micro;g/mL in 0.1 M tris-HCl buffer (pH 8.6). 24 h later since addition of CRMP2 into the wells of the polysterene plate, they were washed four times and the serum samples used as a primary antibody at a dilution rate 1:50 (v/v) in the antibody buffer (0.04 M phosphate buffer (pH 7.3), 015 M NaCl, 0.5 mg/mL of Tween-20 and 1 mg/mL of bovine serum albumin), were added to the wells. 24 h later the wells were washed and the anti-human murine antibody with conjugated horseradish peroxidase used as a secondary antibody at a dilution rate 1:1000 (v/v) in the antibody buffer was added to the wells. 3 h later the wells were washed and peroxidase enzyme substrate \u0026ndash; orthophenylendiamine in 0.05 M phosphate-citrate buffer (pH 4.5) at a concentration of 0.5 mg/mL was added. The plate was placed into a dark compartment and 30 min later the reaction was stopped by adding 50 \u0026micro;L of 3 M NaOH into each well. The results of the reaction were recorded in the photometer for ELISA test \u0026ldquo;Molecular Devices Spectra Max 250\u0026rdquo; (MTX Lab Systems, Inc., USA) at wavelength 492 nm (wavelength of comparison 630 nm).\u003c/p\u003e\u003cp\u003eThe obtained experimental data were analyzed with application of Student\u0026rsquo;s t-criterion and Friedman\u0026rsquo;s χ\u003csup\u003e2\u003c/sup\u003e-criterion.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe depression degrees in the studied patients were evaluated through the Zung Anxiety Rating Scale (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) and Hamilton Anxiety Rating Scale (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) and the patients with minor and major depression degrees were diagnosed. Relative to the middle-aged healthy persons the levels of natural anti-CRMP2 autoantibody in the serum of the minor depression patients increased insignificantly: 0.038\u0026thinsp;\u0026plusmn;\u0026thinsp;0.005 vs. 0.045\u0026thinsp;\u0026plusmn;\u0026thinsp;0.005 optical units of extinction (OUE, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). At the same time, drastic, 50%-decline of the levels of natural anti-CRMP2 autoantibody in the serum of the major depression patients relative to the middle-aged healthy persons was observed (0.019\u0026thinsp;\u0026plusmn;\u0026thinsp;0.002 vs. 0.038\u0026thinsp;\u0026plusmn;\u0026thinsp;0.005 OUE, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01 on Student\u0026rsquo;s t-criterion, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWhile comparing the values of natural anti-CRMP2 autoantibody in the serum of the middle-aged healthy persons, old healthy persons (78\u0026ndash;89 years old) and centenarians (beyond 90 years old), we revealed the very interesting regularity. Relative to the middle-aged healthy persons, the levels of natural anti-CRMP2 autoantibody in the serum of old healthy patients declined prominently (0.038\u0026thinsp;\u0026plusmn;\u0026thinsp;0.005 vs. 0.023\u0026thinsp;\u0026plusmn;\u0026thinsp;0.001 OUE, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 on Friedman\u0026rsquo;s χ\u003csup\u003e2\u003c/sup\u003e-criterion, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). However, the values of natural anti-CRMP2 autoantibody in the serum of the centenarians increased drastically (by 2.3 times) relative to the values of the old healthy persons used in this case as a control group due to their age proximity to the centenarians\u0026rsquo; ages: 0.054\u0026thinsp;\u0026plusmn;\u0026thinsp;0.006 vs. 0.023\u0026thinsp;\u0026plusmn;\u0026thinsp;0.001 OUE (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 on Friedman\u0026rsquo;s χ\u003csup\u003e2\u003c/sup\u003e-criterion, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eOn a whole, the results indicate to insignificant increase of the levels of natural anti-CRMP2 autoantibody in the serum of the minor depression patients and drastic, 50%-decline of their levels in serum of the major depression patients relative to the middle-aged healthy persons. Considering the changes of the levels of natural anti-CRMP2 autoantibody in the serum of persons in relation to aging, prominent decline of their levels in the old healthy persons relative to the middle-aged healthy persons was noted. Conversely, drastic increase of the levels of natural anti-CRMP2 autoantibody in the serum of centenarians relative to the old healthy persons was observed.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe results obtained in this study demonstrate insignificant increase of natural anti-CRMP2 autoantibody levels in the serum of the minor depression patients, whereas 50%-decline of their levels in the serum of the major depression patients relatively to the middle-aged healthy persons was observed. As our earlier studies carried out on the animal depression model showed, the levels of natural anti-CRMP2 autoantibody in the serum reflect CRMP2 levels in the brain subcortical structures (5). Hence, the revealed dynamics of these autoantibody levels indicates indirectly to induction of low-degree adaptation in the brain subcortical structures of the minor depression patients and to manifestation of prominent disadaptation in these structures of the major depression patients. Such conclusion concerning the direct relationship of upregulation of the levels of natural anti-CRMP2 autoantibody in the serum with organism’s adaptation to stressful conditions is made basing on the results of our other earlier studies. In particular, in the serum taken from the patients at the day of an appointed abdominal surgery, the levels of natural anti-CRMP2 autoantibody increased drastically relatively to their levels in the serum of healthy volunteers of the same age (9). Furthermore, in the brains of the originally fresh-water fishes (the semi-migratory fishes Caspian roach (\u003cem\u003eRutilus rutilus caspicus\u003c/em\u003e) and carpbream (\u003cem\u003eAbramis brama orientalis\u003c/em\u003e) and the migratory fish – shemaya\u0026nbsp;(\u003cem\u003eChalcalburnus chalcoides\u003c/em\u003e)) dwelling permanently in brackish water (containing 12‰ NaCl) the levels of serotonin-modulating anticonsolidation protein (SMAP) which included CRMP2 as a constituent protein, increased sharply relative to the fishes of the same species dwelling permanently in the familiar fresh water conditions (10), as well as in the brains of the originally fresh-water common carp (\u003cem\u003eCyprinus carpio L.\u003c/em\u003e) under the effects of brackish water in the model experiments. In the hypothalamus and epiphysis of the Wistar male rats exposed to 14-day uninterrupted light desynchronization, upregulation of CRMP2 was observed (11). In that research two times intranasal CRMP2 administration to the animals of the experimental group with one-week interval brought to a significant decrease of their anxiety behavioral indices in the elevated plus-maze and sharp downregulation of the stress-related hormone cortisol levels in their serum. Hence, all the studies listed above support the idea of upregulation of the levels of CRMP2 in the brain and of natural anti-CRMP2 autoantibody in the serum as a marker of positive adaptation to adverse environmental and intrinsic (psychological) stressful conditions. Consequently, downregulation of the levels of natural anti-CRMP2 autoantibody in the serum of the major depression patients, conversely, might be considered as a marker of poor adaptation or rather disadaptation to stressful conditions experienced by the patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe observed downregulation of the levels of natural anti-CRMP2 autoantibody in the serum of the old-healthy persons relative to the middle-aged healthy persons is, apparently, due to aging-related decline of serotonergic system activity in the human brains and supports the results of other researchers concerning the fading dynamics of serotonergic system in the brains of humans with aging. In particular, serotonin receptors’ density is higher at birth than in the adult brain (12). Furthermore, several post mortem studies on the human brains reported a reduction in the number of cortical 5-HT1A, 5-HT1B/D, and 5-HT2A receptors’ binding sites with aging in frontal lobe, occipital lobe, and hippocampus (13, 14, 15, 16, 17, 18, 19). In addition, the age-related decline in the cortical 5-HT2A binding in alive persons and PET imaging with [11C]N-methylspiperone, an affinity ligand for 5-HT2A, were as well shown (20, 21). Such reduction of the levels of natural anti-CRMP2 autoantibody in the serum of the old-healthy persons, reflecting correspondently the CRMP2 levels in their brain subcortical structures, might be a marker of age-related organism’s senescence and outcoming disadaptation manifestations.\u003c/p\u003e\n\u003cp\u003eConsidering on one line the approximately similar values of the levels of natural anti-CRMP2 autoantibody in the serums of the major depression patients and of the old-healthy persons that undergo the natural senescence process with accompanying fading dynamics of the serotonergic system activity in their brain subcortical structures, the conclusion concerning the basic decline of serotonergic system activity in those structures of the major depression patients as a pre-term, accelerated aging following disadaptation process to social environmental conditions might be done.\u003c/p\u003e\n\u003cp\u003eThe unexpected, as it may appear to a first glance, sharp upregulation of the levels of natural anti-CRMP2 autoantibody in the serum of the centenarians relative to the old-healthy persons as an age-adequate control group, apparently, indicates to the correspondent upregulation of CRMP2 in the centenarians’ brain subcortical structures. This result gives valid grounds to making a conclusion concerning a formation of high adaptation potential in the members of this age group. Such conclusion is, actually, supported by other researchers of a big cohort of centenarians, who demonstrated two times less incidence of depression manifestations relative to the octogenarians, comprising 81-90-age-old life interval (22), and this way proved the existence of their higher level of adaptation to the social conditions and the higher level of optimistic mood in comparison to the octogenarians.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics declaration.\u0026nbsp;\u003c/strong\u003eAll tests on humans were carried out in agreement with the existing International Ethical Principles. Written consent was obtained from all participants of the above tests. The ethical approval was obtained from the Ethics Committee of the Academician Abdulla Garayev Institute of Physiology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of potential conflicts of interest.\u0026nbsp;\u003c/strong\u003eThe authors state of absence of any potential conflict of interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding source.\u0026nbsp;\u003c/strong\u003eThere was no funding source in conducting the described studies.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eCollins CM, Kloek J, Elliott JM. (2013): Parallel changes in serotonin levels in brain and blood following acute administration of MDMA. \u003cem\u003eJ Psychopharmacol\u003c/em\u003e 27: 109\u0026ndash;112. DOI: 10.1177/0269881112463123\u003c/li\u003e\n \u003cli\u003eElliott JM, Kent A. (1989): Comparison of [125I]iodolysergic acid diethylamide binding in human frontal cortex and platelet tissue. \u003cem\u003eJ Neurochem\u003c/em\u003e 53: 191\u0026ndash;196. DOI: 10.1111/j.1471-4159\u003c/li\u003e\n \u003cli\u003eLacroix-Desmazes S, Kaveri SV, \u0026nbsp;Mouthon L, \u0026nbsp; Ayouba A, Malachere E, Coutinho A, Kazaychkine MD. (1998): Self-reactive natural autoantibodies in healthy individuals. \u003cem\u003eJ Immunology Methods\u003c/em\u003e 216:117-137.\u003c/li\u003e\n \u003cli\u003eMekhtiev AA, Ismailova US.\u0026nbsp;(2021): Central serotonergıc trophıc support of retına and ıts ımpaırment ın retınıtıs pıgmentosa on anımal model and clınıcs.\u0026nbsp;\u003cem\u003eJ Neurophysiology\u003c/em\u003e 52: 30-38.\u003c/li\u003e\n \u003cli\u003eHasanova LF. (2022): The changes of serotonin-modulating anticonsolidation protein and dihydropyrimidinase-related protein 2 in the amygdala and blood of depressive rats. \u003cem\u003eAzerbaijan J Physiol\u003c/em\u003e 37: 7\u0026ndash;12. DOI: 10.59883/ajp.37\u003c/li\u003e\n \u003cli\u003eInagaki N, Chihara K, Arimura N, M\u0026eacute;nager C, Kawano MN, \u003cem\u003eet al.\u003c/em\u003e (2001): CRMP-2 induces axons in cultured hippocampal neurons. \u003cem\u003eNature Neuroscience\u003c/em\u003e 4:781\u0026ndash;782.\u003c/li\u003e\n \u003cli\u003eDunstan DA, Scott N. (2020): Norms for Zung\u0026apos;s Self-rating Anxiety Scale. \u003cem\u003eBMC Psychiatry\u003c/em\u003e 20:90. doi: 10.1186/s12888-019-2427-6.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThompson E. (2015): Hamilton Rating Scale for Anxiety (HAM-A). \u003cem\u003eOccupational Medicine\u003c/em\u003e 65: 601. DOI: 10.1093/occmed/kqv054\u003c/li\u003e\n \u003cli\u003eGuliyeva ShM, Mekhtiev AA.\u0026nbsp;(2023): Engagement of dihydropyrimidinase-related protein 2 in regulation of anxiety in humans. \u003cem\u003eI.M.Sechenov Russian Journal Physiol\u003c/em\u003e 108:34-45.\u003c/li\u003e\n \u003cli\u003eMustafayev NJ, Mekhtiev AA. (2013): Adaptive increase of serotonergic system activity in tissues of half-migratory and migratory fish at increased water salinity. \u003cem\u003eJ Evol Biochem Physiol\u003c/em\u003e 49: 443-448.\u003c/li\u003e\n \u003cli\u003eZulfugarova P, Mekhtiev AA. (2024): Central and hormonal mechanisms of adaptation to desynchronization stress. \u003cem\u003eIntegrative Physiology\u003c/em\u003e 5(2):34-41.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAzmitia EC, Whitaker-Azmitia PM. (1991): Awakening the sleeping giant: Anatomy and plasticity of the brain serotonergic system. \u003cem\u003eJ Clin Psychiatry\u003c/em\u003e 52: 4\u0026ndash;16.\u003c/li\u003e\n \u003cli\u003eArranz B, Eriksson A, Mellerup E, Plenge P, Marcusson J. (1993): Effect of aging in human cortical pre- and postsynaptic serotonin binding sites. \u003cem\u003eBrain Res\u003c/em\u003e 620: 163\u0026ndash;166.\u003c/li\u003e\n \u003cli\u003eCheetham S, Crompton M, Katona C, Horton R. (1988): Brain 5-HT2 receptor binding sites in depressed suicide victims. \u003cem\u003eBrain Res\u003c/em\u003e\u0026nbsp; 443: 272\u0026ndash;280.\u003c/li\u003e\n \u003cli\u003eGross-Isseroff R, Salama D, Isreli M, Biegon A. (1990): Autoradiographic analysis of [3H]ketansterin binding in the human brain postmortem: effect of suicide. \u003cem\u003eBrain Res\u003c/em\u003e 507: 208\u0026ndash;215.\u003c/li\u003e\n \u003cli\u003eMarcusson J, Morgan D, Winblad B, Finch C. (1984): Serotonin-2 binding sites in human frontal cortex and hippocampus. Selective loss of S-2A sites with age. \u003cem\u003eBrain Res\u003c/em\u003e 311: 51\u0026ndash;56.\u003c/li\u003e\n \u003cli\u003eMarcusson J, Oreland L, Winblad B. (1984): Effect of age on human brain serotonin (S-1) binding sites. \u003cem\u003eJ Neurochem\u003c/em\u003e\u0026nbsp; 43: 1699\u0026ndash;1705.\u003c/li\u003e\n \u003cli\u003eShih J, Young H. (1978): The alteration of serotonin binding sites in aged human brained. \u003cem\u003eLife Sci\u003c/em\u003e 23: 1441\u0026ndash;1448.\u003c/li\u003e\n \u003cli\u003eSparks D. (1989): Aging and Alzheimer\u0026apos;s disease. Altered cortical serotonergic binding. \u003cem\u003eArch Neurol\u003c/em\u003e\u0026nbsp; 46: 138\u0026ndash;140.\u003c/li\u003e\n \u003cli\u003eIyo M, Yamasaki T. (1993): The detection of age-related decrease of dopamine D1, D2 and serotonin 5-HT2 receptors in living human brain. \u003cem\u003eProg Neuro-Psychopharmacol Biol Psychiatry\u003c/em\u003e 17: 415\u0026ndash;421.\u003c/li\u003e\n \u003cli\u003eWong D, Wagner HJ, Dannals R, Links J, Frost J, Ravert H, \u003cem\u003eet al.\u003c/em\u003e (1984): Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain. \u003cem\u003eScience\u003c/em\u003e 226: 1393\u0026ndash;1396.\u003c/li\u003e\n \u003cli\u003eMargrett J, Martin P, Woodard JL, Miller LS, MacDonald M, Baenziger J, \u003cem\u003eet al.\u003c/em\u003e (2010): Depression among centenarians and the oldest old: contributions of cognition and personality. \u003cem\u003eGerontology\u003c/em\u003e 56: 93-9. DOI: 10.1159/000272018.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"neurophysiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Neurophysiology](https://link.springer.com/journal/11062)","snPcode":"11062","submissionUrl":"https://submission.springernature.com/new-submission/11062/3","title":"Neurophysiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"natural autoantibody to collapsin-response mediator protein 2 (CRMP2), serum, minor and major depression patients, old healthy persons, centenarians","lastPublishedDoi":"10.21203/rs.3.rs-7507990/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7507990/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground. \u003c/strong\u003eThe article concerns the study of the levels of natural autoantibody to collapsin-response mediator protein 2 (CRMP2) in the serum of the minor and major depression patients, old healthy persons and centenarians.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods.\u003c/strong\u003e The purified CRMP2 was used as antigen and obtained serum samples were used as the primary antibody in an indirect ELISA test.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults. \u003c/strong\u003eThe results revealed insignificant increase of the autoantibody levels in the serum of the minor depression patients and drastic, 50%-decline of their levels in the serum of the major depression patients (\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.01 on Student’s t-criterion) relative to the middle-aged healthy persons. While comparing the values of natural anti-CRMP2 autoantibody in the serum of the middle-aged healthy persons, old healthy persons (78-89 years old) and centenarians (beyond 90 years old), we revealed the following regularity. Relative to the middle-aged healthy persons, the levels of anti-CRMP2 autoantibody in the serum of old healthy patients declined prominently (\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.001 on Friedman’s χ\u003csup\u003e2\u003c/sup\u003e-criterion). However, the values of anti-CRMP2 autoantibody in the serum of the centenarians increased drastically (by 2.3 times) relative to the values of the old healthy persons used as a control group (\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.001 on Friedman’s χ\u003csup\u003e2\u003c/sup\u003e-criterion).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion. \u003c/strong\u003eThe conclusion concerning reliability of evaluation of the levels of natural anti-CRMP2 autoantibody in the serum of the humans as an adaptation marker and consideration of the molecular mechanisms of major depression as the underlying mechanisms of pre-term aging is made.\u003c/p\u003e","manuscriptTitle":"Collapsin-response Mediator Protein 2 as a Marker of Adaptation and Disadaptation in Humans: Study on Depression Patients and Centenarians","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-12 14:44:16","doi":"10.21203/rs.3.rs-7507990/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-01T20:58:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-01T20:19:36+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-27T07:57:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"240313323327765703149139831902169810677","date":"2025-11-21T18:54:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"124894451677112398489322470064429143626","date":"2025-11-21T18:02:28+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-06T12:05:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-06T11:14:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-06T11:13:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Neurophysiology","date":"2025-09-01T11:36:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"neurophysiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Neurophysiology](https://link.springer.com/journal/11062)","snPcode":"11062","submissionUrl":"https://submission.springernature.com/new-submission/11062/3","title":"Neurophysiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e44ef19a-19be-4902-8db3-6808aab6ca7f","owner":[],"postedDate":"September 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-05T19:39:22+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-12 14:44:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7507990","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7507990","identity":"rs-7507990","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}