engleski

The chronic stress response is sex and age specific

Introduction: A unique animal model of sex and age specific chronic stress was developed that implies strong chronic stress resistance of young animals and the strongest impact in older females. This model is oriented to CNS and implies that stress regulation in the brain is sex and age specific. The main hypothesis of this study proposes that aging and stress combined lead towards changes in lipid rafts composition of brain and trigger neurodegeneration. Methods: Male and female Sprague Dawley rats were divided in young (6, 5 months old) and old (14, 5 months old) groups. Chronic stress protocol was performed for 10 weeks. Hippocampi and cerebella were analyzed by various methods. Lipid rafts were isolated and tested by Western blot, tissue was stained by HRP/DAB immunohistochemistry and immunofluorescence. Insulin (IR), leptin (ObR), estrogen (ER), AMPA (AMPAR) and glucocorticoid (GR) receptors, amyloid precursor protein (APP), Tau, GM1, GD1a and neuroplastin (Np) were analyzed. Memory impairment was tested by passive avoidance test, mass spectrometry was used for steroid hormones analyses. All data was analyzed by the Statistica software. Results: Observed changes in steroid hormones strongly validate the chronic stress protocol – corticosterone is increased in young males and old females upon stress. Neuroprotection by progesterone upon stress was observed in old females. Testosterone showed the same trend in old stressed males. The older females showed memory impairment and reduced insulin, AMPA receptors in hippocampus. ObR expression was increased upon stress in older animals and could be a potential neuroprotection activator. Lipid content changes of lipid rafts upon stress were noticed as GM1 ganglioside increase in CA1 and dentate gyrus of hippocampus of young animals and increase of GD1a in CA1 region of hippocampus of all chronically stressed animal groups. Also, colocalization of APP and GD1a was observed in hippocampus of older females just upon chronic stress. Discussion and conclusion: Decrease of IR and ObR expression is accompanied by AMPA receptor and Np decrease. We propose connection of leptin and insulin signaling with pathways involved with neuroplasticity. Acknowledgments: This study has been funded by Croatian Science Foundation (IP-09-2014-2324), The European Union through European Regional Development Fund, Operational Programme Competitiveness and Cohesion, grant agreement No. KK.01.1.1.01.0007, CoRE – Neuro and Cedars Sinai Medical Center’s International Research and Innovation in Medicine Program and the RECOOP HST Association. Part of this study was performed at the Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, under the supervision of prof. Robert Gaspar. Ethical Committee Approval: Experiments were carried out at Animal Facility of Faculty of Medicine Osijek and was approved under class number 602-04/14-08/06 and registration number 2158-61-07-14-118 and Animal Facility of Faculty of Pharmacy, Szeged, approval number: CSI/01/3796-7/2015.

chronic stress, neurodegeneration

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