Abstract
An important factor that may affect the severity and time of onset of Alzheimer's disease (AD) is chronic stress. Epidemiological studies report that chronically stressed individuals are at an increased risk for developing AD. The purpose of this study was to reveal whether chronic psychosocial stress could hasten the appearance of AD symptoms including changes in basal levels of cognition-related signaling molecules in subjects who are at risk for the disease. We investigated the effect of chronic psychosocial stress on basal levels of memory-related signaling molecules in area CA1 of subclinical rat model of AD. The subclinical symptomless rat model of AD was induced by osmotic pump continuous intracerebroventricular (ICV) infusion of 160 pmol/day Aβ1–42 for 14 days. Rats were chronically stressed using the psychosocial stress intruder model. Western blot analysis of basal protein levels of important signaling molecules in hippocampal area CA1 showed no significant difference between the subclinical AD rat model and control rat. Following six weeks of psychosocial stress, molecular analysis showed that subclinical animals subjected to stress have significantly reduced basal levels of p-CaMKII and decreased p-CaMKII/t-CaMKII ratio as well as decreased basal levels of p-CREB, total CREB, and BDNF. The present results suggest that these changes in basal levels of signaling molecules may be responsible for impaired learning, memory, and LTP in this rat model, which support the proposition that chronic stress may accelerate the emergence of AD in susceptible individuals.
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Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB et al (1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359:322–325
Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37:925–937
Goodman Y, Mattson MP (1994) Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury. Exp Neurol 128:1–12
Green PS, Gridley KE, Simpkins JW (1996) Estradiol protects against beta-amyloid (25–35)-induced toxicity in SK-N-SH human neuroblastoma cells. Neurosci Lett 218:165–168
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 95(11):6448–53
Assis-Nascimento P, Jarvis KM, Montague JR, Mudd LM (2007) Beta-amyloid toxicity in embryonic rat astrocytes. Neurochem Res 32:1476–1482
Cullen WK, Suh YH, Anwyl R, Rowan MJ (1997) Block of LTP in rat hippocampus in vivo by beta-amyloid precursor protein fragments. Neuroreport 8:3213–3217
Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol 155:853–862
Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC (2004) Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62:925–931
Carrotta R, Di Carlo M, Manno M, Montana G, Picone P, Romancino D, San Biagio PL (2006) Toxicity of recombinant beta-amyloid prefibrillar oligomers on the morphogenesis of the sea urchin Paracentrotus lividus. FASEB J 20:1916–1917
Tran TT, Srivareerat M, Alkadhi KA (2010) Chronic psychosocial stress triggers cognitive impairment in a novel at-risk model of Alzheimer's disease. Neurobiol Dis 37:756–763
Tran TT, Srivareerat M, Alkadhi KA (2011) Chronic psychosocial stress accelerates impairment of long-term memory and late-phase long-term potentiation in an at-risk model of Alzheimer’s disease. Hippocampus 21:724–732
Tran TT, Srivareerat M, Alhaider IA, Alkadhi KA (2011) Chronic stress enhances long-term depression in a subthreshold amyloid-beta rat model of Alzheimer’s disease. J Neurochem 119:408–416
Srivareerat M, Tran TT, Alzoubi KH, Alkadhi KA (2009) Chronic psychosocial stress exacerbates impairment of cognition and long-term potentiation in beta-amyloid rat model of Alzheimer's disease. Biol Psychiatry 65:918–926
Alkadhi KA, Srivareerat M, Tran TT (2010) Intensification of long-term memory deficit by chronic stress and prevention by nicotine in a rat model of Alzheimer’s disease. Mole Cell Neurosci 45:289–296
Alkadhi KA, Alzoubi KH, Srivareerat M, Tran TT (2011) Chronic psychosocial stress exacerbates impairment of synaptic plasticity in beta-amyloid rat model of Alzheimer’s disease: prevention by nicotine. Curr Alzheimer Res 8:718–731
Hartmann A, Veldhuis JD, Deuschle M, Standhardt H, Heuser I (1997) Twenty-four hour cortisol release profiles in patients with Alzheimer's and Parkinson's disease compared to normal controls: ultradian secretory pulsatility and diurnal variation. Neurobiol Aging 18:285–289
de Bruin VM, Vieira MC, Rocha MN, Viana GS (2002) Cortisol and dehydroepiandrosterone sulfate plasma levels and their relationship to aging, cognitive function, and dementia. Brain Cogn 50:316–323
Armanini D, Vecchio F, Basso A, Milone FF, Simoncini M, Fiore C, Mattarello MJ, Sartorato P, Karbowiak I (2003) Alzheimer's disease: pathophysiological implications of measurement of plasma cortisol, plasma dehydroepiandrosterone sulfate, and lymphocytic corticosteroid receptors. Endocrine 22:113–118
Csernansky JG, Dong H, Fagan AM, Wang L, Xiong C, Holtzman DM, Morris JC (2006) Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am J Psychiatry 163:2164–2169
Deshmukh VD, Deshmukh SV (1990) Stress-adaptation failure hypothesis of Alzheimer's disease. Med Hypotheses 32:293–295
Sauro MD, Jorgensen RS, Pedlow CT (2003) Stress, glucocorticoids, and memory: a meta-analytic review. Stress 6:235–245
Landfield PW, Blalock EM, Chen KC, Porter NM (2007) A new glucocorticoid hypothesis of brain aging: implications for Alzheimer's disease. Curr Alzheimer Res 4:205–212
Wilson RS, Schneider JA, Boyle PA, Arnold SE, Tang Y, Bennett DA (2007) Chronic distress and incidence of mild cognitive impairment. Neurology 68:2085–2092
Gerges NZ, Stringer JL, Alkadhi KA (2001) Combination of hypothyroidism and stress abolishes early LTP in the CA1 but not dentate gyrus of hippocampus of adult rats. Brain Res 922:250–260
Aleisa AM, Alzoubi KH, Alkadhi KA (2006) Chronic but not acute nicotine treatment reverses stress-induced impairment of LTP in anesthetized rats. Brain Res 1097:78–84
Alkadhi KA, Hogan YH, Tanner FL (1998) Inhibition of ganglionic LTP prevents stress-induced hypertension in rats. Naunyn Schmiedebergs Arch Pharmacol 358:R265
Dao AT, Zagaar MA, Levine AT, Salim S, Eriksen JL, Alkadhi KA (2013) Treadmill exercise prevents learning and memory impairment in Alzheimer’s disease-like pathology. Curr Alzheimer Res 10(5):507–515
Dao AT, Zagaar MA, Salim S, Eriksen JL, Alkadhi KA (2014) Regular exercise prevents non-cognitive disturbances in a rat model of Alzheimer’s disease. Int J Neuropsychopharmacol 17(4):593–602
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic, Sydney
Zagaar M, Alhaider IA, Dao A, Levine A, Alkadhi KA (2013) Regular exercise prevents sleep deprivation associated impairment of long-term memory, synaptic plasticity and its signaling cascade in the CA1 area of the hippocampus. Sleep 36(5):751–761
Zagaar M, Dao A, Levine A, Alhaider IA, Salim S, Alkadhi KA (2013) Regular treadmill exercise prevents sleep loss induced deficits in synaptic plasticity and its signaling cascade in the dentate gyrus. Mol Cell Neuroscience 56:375–383
Zagaar M, Alhaider IA, Dao A, Levine A, Alkarawi A, Alzubaidy M, Alkadhi KA (2012) The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence. Neurobiol Dis 45:1153–1162
Giese KP, Fedorov NB, Filipkowski RK, Silva AJ (1998) Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science 279:870–873
Lisman J, Schulman H, Cline H (2002) The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 3:175–190
Colbran RJ, Brown AM (2004) Calcium/calmodulin-dependent protein kinase II and synaptic plasticity. Curr Opin Neurobiol 14:318–327
Mansuy IM (2003) Calcineurin in memory and bidirectional plasticity. Biochem Biophys Res Commun 311:1195–1208
Hoeffer CA, Wong H, Cain P, Levenga J, Cowansage KK, Choi Y, Davy C, Majmundar N, McMillan DR, Rothermel BA, Klann E (2013) Regulator of calcineurin 1 modulates expression of innate anxiety and anxiogenic responses to selective serotonin reuptake inhibitor treatment. J Neurosci 33(43):16930–16944
Nitta A, Itoh A, Hasegawa T, Nabeshima T (1994) beta-Amyloid protein-induced Alzheimer's disease animal model. Neurosci Lett 170:63–66
Nitta A, Fukuta T, Hasegawa T, Nabeshima T (1997) Continuous infusion of beta-amyloid protein into the rat cerebral ventricle induces learning impairment and neuronal and morphological degeneration. Jpn J Pharmacol 73:51–57
Oka J, Suzuki E, Kondo Y (2000) Endogenous GLP-1 is involved in beta-amyloid protein-induced memory impairment and hippocampal neuronal death in rats. Brain Res 878:194–198
Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG (2004) Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience 127:601–609
Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM (2006) Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer’s disease. J Neurosci 26:9047–9056
Jeong YH, Park CH, Yoo J, Shin KY, Ahn SM, Kim HS, Lee SH, Emson PC, Suh YH (2006) Chronic stress accelerates learning and memory impairments and increases amyloid deposition in APPV717I-CT100 transgenic mice, an Alzheimer’s disease model. Faseb J 20:729–731
Peavy GM, Lange KL, Salmon DP, Patterson TL, Goldman S, Gamst AC et al (2007) The effects of prolonged stress and APOE genotype on memory and cortisol in older adults. Biol Psychiatry 62:472–478
Alzoubi KH, Abdul-Razzak KK, Khabour OF, Al-Tuweiq GM, Alzubi MA, Alkadhi KA (2009) Adverse effect of combination of chronic psychosocial stress and high fat diet on hippocampus-dependent memory in rats. Behav Brain Res 204:117–123
Huether G (1996) The central adaptation syndrome: psychosocial stress as a trigger for adaptive modifications of brain structure and brain function. Prog Neurobiol 48:569–612
Miller DB, O'Callaghan JP (2002) Neuroendocrine aspects of the response to stress. Metabolism 51:5–10
Tsigos C, Chrousos GP (2002) Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res 53:865–871
Townsend M, Mehta T, Selkoe DJ (2007) Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem 282:33305–33312
McEwen BS (1999) Stress and the aging hippocampus. Front Neuroendocrinol 20:49–70
Pavlides C, Watanabe Y, Magarinos AM, McEwen BS (1995) Opposing roles of type I and type II adrenal steroid receptors in hippocampal long-term potentiation. Neuroscience 68:387–394
Kim JJ, Yoon KS (1998) Stress: metaplastic effects in the hippocampus. Trends Neurosci 21:505–509
Silva AJ, Kogan JH, Frankland PW, Kida S (1998) CREB and memory. Annu Rev Neurosci 21:127–148
Carlezon WA Jr, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends Neurosci 28:436–445
Lamprecht R (1999) CREB: a message to remember. Cell Mol Life Sci 55:554–563
Walton MR, Dragunow I (2000) Is CREB a key to neuronal survival? Trends Neurosci 23:48–53
Ito H, Takemoto-Kimura S (2003) Ca(2+)/CREB/CBP-dependent gene regulation: a shared mechanism critical in long-term synaptic plasticity and neuronal survival. Cell Calcium 34:425–430
Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ (1994) Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79:59–68
Yin JC, Del Vecchio M, Zhou H, Tully T (1995) CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 81:107–115
Ma QL, Harris-White ME, Ubeda OJ, Simmons M, Beech W, Lim GP, Teter B, Frautschy SA, Cole GM (2007) Evidence of Abeta- and transgene-dependent defects in ERK-CREB signaling in Alzheimer's models. J Neurochem 103:1594–1607
Yamin G (2009) NMDA receptor-dependent signaling pathways that underlie amyloid
Arvanitis DN, Ducatenzeiler A, Ou JN, Grodstein E, Andrews SD, Tendulkar SR, Ribeiro-da-Silva A, Szyf M, Cuello AC (2007) High intracellular concentrations of amyloid-beta block nuclear translocation of phosphorylated CREB. J Neurochem 103:216–228
Davies KJ, Ermak G, Rothermel BA, Pritchard M, Heitman J, Ahnn J, Henrique-Silva F, Crawford D, Canaider S, Strippoli P, Carinci P, Min KT, Fox DS, Cunningham KW, Bassel-Duby R, Olson EN, Zhang Z, Williams RS, Gerber HP, Pérez-Riba M, Seo H, Cao X, Klee CB, Redondo JM, Maltais LJ, Bruford EA, Povey S, Molkentin JD, McKeon FD, Duh EJ, Crabtree GR, Cyert MS, de la Luna S, Estivill X (2007) Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin. FASEB J 21(12):3023–3028
Klee CB, Crouch TH, Krinks MH (1979) Calcineurin: a calcium- and calmodulin-binding protein of the nervous system. Proc Natl Acad Sci U S A 76:6270–6273
Groth RD, Dunbar RL, Mermelstein PG (2003) Calcineurin regulation of neuronal plasticity. Biochem Biophys Res Commun 311:1159–1171
Gerges NZ, Alzoubi KH, Alkadhi KA (2005) Role of phosphorylated CaMKII and calcineurin in the differential effect of hypothyroidism on LTP of CA1 and dentate gyrus. Hippocampus 15:480–490
Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Neuron 7:695–702
Connor B, Young D, Yan Q, Faull RL, Synek B, Dragunow M (1997) Brain-derived neurotrophic factor is reduced in Alzheimer's disease. Brain Res Mol Brain Res 49:71–81
Lipsky RH, Marini AM (2007) Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann N Y Acad Sci 1122:130–143
Barco A, Patterson S, Alarcon JM, Gromova P, Mata-Roig M, Morozov A, Kandel ER (2005) Gene expression profiling of facilitated L-LTP in VP16-CREB mice reveals that BDNF is critical for the maintenance of LTP and its synaptic capture. Neuron 48:123–137
Alzoubi KH, Aleisa AM, Alkadhi KA (2007) Adult-onset hypothyroidism facilitates and enhances LTD: reversal by chronic nicotine treatment. Neurobiol Dis 26:264–272
Alzoubi KH, Aleisa AM, Alkadhi KA (2007) Nicotine prevents disruption of the late phase LTP-related molecular cascade in adult-onset hypothyroidism. Hippocampus 17:654–664
Kang H, Welcher AA, Shelton D, Schuman EM (1997) Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron 19:653–664
Minichiello L, Calella AM, Medina DL, Bonhoeffer T, Klein R, Korte M (2002) Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 36:121–137
Pang PT, Lu B (2004) Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF. Ageing Res Rev 3:407–430
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Alkadhi, K.A., Tran, T.T. Chronic Stress Decreases Basal Levels of Memory-Related Signaling Molecules in Area CA1 of At-Risk (Subclinical) Model of Alzheimer’s Disease. Mol Neurobiol 52, 93–100 (2015). https://doi.org/10.1007/s12035-014-8839-x
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DOI: https://doi.org/10.1007/s12035-014-8839-x