Chronic psychosocial stress reveals Alzheimer’s disease in a novel at-risk rat model
Keywords:rat AD model, amyloid-beta, learning and memory, signaling molecules
Extensive individual variations in the time of onset and severity of the sporadic type of Alzheimer’s disease (AD), may be due to some patient-related external factors. Stress is increasingly recognized as an external factor in the development of AD. Several labs, including mine, have demonstrated that chronic stress or corticosterone administration aggravates the disease in both transgenic and non-transgenic animal models. We have developed a novel rat model that simulates seemingly normal individuals who are predisposed to develop AD. This review summarizes the findings we have reported on the effect of chronic psychosocial stress in this at-risk model of AD. Behavioral (learning and memory tests), electrophysiological (evoked long-term potentiation) and molecular (protein levels of memory-related signaling molecules a well as AD-related molecules. Our findings suggest that even mild psychosocial stress noticeably transforms this seemingly normal rat model to a full-fledge AD phenotype.
Tanzi RE, Bertram L. 2005. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120:545-555.
Castellani RJ, Lee HG, Zhu X, Perry G, Smith MA. 2008. Alzheimer disease pathology as a host response. J Neuropathol Exp Neurol 67:523-531.
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.
Srivareerat M, Tran TT, Salim S, Aleisa AM, Alkadhi KA. 2011. Chronic nicotine restores normal Abeta levels and prevents short-term memory and E-LTP impairment in Abeta rat model of Alzheimer's disease. Neurobiol Aging 32:834-844.
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. Molecular Cell Neurosci 45:289-296
Alkadhi KA. 2012. Chronic psychosocial stress exposes Alzheimer's disease phenotype in a novel at-risk model. Front Biosci (Elite Ed) (invited Review)) 4:214-229
Mesulam MM (1999) Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles. Neuron 24:521-529.
Rowan MJ, Klyubin I, Cullen WK, Anwyl R. 2003. Synaptic plasticity in animal models of early Alzheimer's disease. Philos Trans R Soc Lond B Biol Sci 358:821-828.
Selkoe DJ, 2004. Alzheimer disease: mechanistic understanding predicts novel therapies. Ann Intern Med 140:627-638.
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL and Selkoe DJ. 2008. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14: 837-842.
Sakono M, Zako T. 2010. Amyloid oligomers: formation and toxicity of Abeta oligomers. FEBS J. 277(6):1348-1358.
Walker E, Mittal V, Tessner K. 2008. Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia. Annu Rev Clin Psychol 4:189-216.
Whitworth JA, Mangos GJ, Kelly JJ. 2000. Cushing, cortisol, and cardiovascular disease. Hypertension 36:912-916
Gerges NZ, Aleisa AM, Schwarz LA, Alkadhi KA. 2004a. Reduced basal CaMKII levels in hippocampal CA1 region: possible cause of stress-induced impairment of LTP in chronically stressed rats. Hippocampus 14:402-410.
Gerges NZ, Alzoubi KH, Park CR, Diamond DM, Alkadhi KA. 2004b. Adverse effect of the combination of hypothyroidism and chronic psychosocial stress on hippocampus-dependent memory in rats. Behav Brain Res 155:77-84.
Alzoubi KH, Aleisa AM, and Alkadhi KA. 2008. Effect of chronic stress or nicotine on hypothyroidism–induced enhancement of LTD: electrophysiological and molecular studies. Neurobiol. Disease 32(1):81-87.
Elgh E, Lindqvist Astot A, Fagerlund M, Eriksson S, Olsson T, Näsman B. 2006. Cognitive dysfunction, hippocampal atrophy and glucocorticoid feedback in Alzheimer's disease. Biol Psychiatry.;59(2):155-161.
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.
Budas G, Coughlan CM, Seckl JR, Breen KC. 1999. The effect of corticosteroids on amyloid beta precursor protein/amyloid precursor-like protein expression and processing in vivo. Neurosci Lett; 276(1):61-64.
Islam A, Kalaria RN, Winblad B, Adem A. 1998. Enhanced localization of amyloid beta precursor protein in the rat hippocampus following long-term adrenalectomy. Brain Res; 806: 108–112.
Wilson RS, Evans DA, Bienias JL, Mendes de Leon CF, Schneider JA, Bennett DA. 2003. Proneness to psychological distress is associated with risk of Alzheimer's disease. Neurology 61:1479-1485
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
McEwen BS. 2008. Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators. Eur J Pharmacol 583:174-185.
Alkadhi KA. 2011. Chronic stress and Alzheimer’s disease-like pathogenesis in a rat model: Prevention by nicotine. Current Neuropharmacology (Alkadhi KA and Eriksen J : Issue Eds): Neurodegeneration “Hot Topic” issue) 9:587-597
Pepeu G, Giovannelli L, Casamenti F, Scali C, Bartolini L. 1996. Amyloid beta-peptides injection into the cholinergic nuclei: morphological, neurochemical and behavioral effects. Prog Brain Res 109:273-282.
Nabeshima T, Itoh A. 1998. Toxicity of beta-amyloid peptide. J Toxicol Sci 23 Suppl 2:177-180.
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 95:6448-6453.
Assis-Nascimento P, Jarvis KM, Montague JR, Mudd LM. 2007. Beta-amyloid toxicity in embryonic rat astrocytes. Neurochem Res 32:1476-1482.
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.
Aleisa AM, Alzoubi KH, Gerges NZ, Alkadhi KA. 2006c. Chronic psychosocial stress-induced impairment of hippocampal LTP: possible role of BDNF. Neurobiol Dis 22:453-462.
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(2):250–260Res 922(2):250–260
Alkadhi KA, Alzoubi KH, Aleisa AM, Tanner FL, Nimer AS. 2005. Psychosocial stress-induced hypertension results from in vivo expression of long-term potentiation in rat sympathetic ganglia. Neurobiol Dis. Dec;20(3):849-857.
Alamed, J., Wilcock, D. M., Diamond, D. M., Gordon, M. N., & Morgan, D. 2006. Two-day radial-arm water maze learning and memory task; robust resolution of amyloid-related memory deficits in transgenic mice. Nature Protocols, 1, 1671–1679.
Hodges H. 1996. Maze procedures: the radial-arm and water maze compared. Brain Res Cogn Brain Res 3:167-181.
Diamond DM, Park CR, Heman KL, Rose GM. 1999. Exposing rats to a predator impairs spatial working memory in the radial arm water maze. Hippocampus 9:542-552.
Aleisa AM, Alzoubi KH, Alkadhi KA. 2006b. Nicotine prevents stress-induced enhancement of long-term depression in hippocampal area CA1: Electrophysiological and molecular studies. J Neurosci Res 83:309-317.
Novak G, Fan T, O'Dowd BF, George SR. 2013. Postnatal maternal deprivation and pubertal stress have additive effects on dopamine D2 receptor and CaMKII beta expression in the striatum. Int J Dev Neurosci. May;31(3):189-195
Malenka RC, Kauer JA, Perkel DJ, Mauk MD, Kelly PT, Nicoll RA, Waxham MN. 1989. An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature. 17;340(6234):554-557.
Nicoll RA, Malenka RC, Kauer JA. 1989. The role of calcium in long-term potentiation. Ann N Y Acad Sci. 568:166-170
Fukunaga K, Stoppini L, Miyamoto E, Muller D. 1993. Long-term potentiation is associated with an increased activity of Ca2+/calmodulin-dependent protein kinase II. J Biol Chem 268:7863-7867.
Kim JJ, Yoon KS. 1998. Stress: metaplastic effects in the hippocampus. Trends Neurosci 21:505-509.
Gerendasy DD, Sutcliffe JG. 1997. RC3/neurogranin, a postsynaptic calpacitin for setting the response threshold to calcium influxes. Mol Neurobiol 15:131-163.
Wang JH, Kelly PT. 1995. Postsynaptic injection of CA2+/CaM induces synaptic potentiation requiring CaMKII and PKC activity. Neuron 15:443-452
Holmes, WR. 2000. Models of calmodulin trapping and CaM kinase II activation in a dendritic spine. J Comput Neurosci 8(1): 65-85.
Fukunaga K, Muller D, Miyamoto E. 1996. CaMkinase II in long-term potentiation. Neurochem Int 28:343-358
Nayak AS, Moore CI, Browning MD. 1996. Ca2+/calmodulin-dependent protein kinase II phosphorylation of the presynaptic protein synapsin I is persistently increased during long-term potentiation. Proc Natl Acad Sci U S A 93:15451-15456.
Barria A, Derkach V, Soderling T. 1997. Identification of the Ca2+/calmodulin-dependent protein kinase II regulatory phosphorylation site in the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-type glutamate receptor. J Biol Chem 272:32727-32730.
Wang JH, Kelly PT. 1996. Regulation of synaptic facilitation by postsynaptic Ca2+/CaM pathways in hippocampal CA1 neurons. J Neurophysiol. 76(1):276-286.
Fukunaga K, Miyamoto E. 2000. A working model of CaM kinase II activity in hippocampal long-term potentiation and memory. Neurosci Res 38:3-17.
Lisman J, Schulman H, Cline H. 2002. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 3:175-190.
Mulkey RM, Endo S, Shenolikar S, Malenka RC. 1994. Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 369:486-488.
Strack S, Barban MA, Wadzinski BE, Colbran RJ. 1997. Differential inactivation of postsynaptic density-associated and soluble Ca2+/calmodulin-dependent protein kinase II by protein phosphatases 1 and 2A. J Neurochem. 68(5):2119-2128
Thiels E, Kanterewicz BI, Knapp LT, Barrionuevo G, Klann E. 2000. Protein phosphatase-mediated regulation of protein kinase C during long-term depression in the adult hippocampus in vivo. J Neurosci. 20(19):7199-7207.
Wang JH, Kelly PT. 1997. Postsynaptic calcineurin activity downregulates synaptic transmission by weakening intracellular Ca2+ signaling mechanisms in hippocampal CA1 neurons. J Neurosci. 17(12):4600-4611
Winder, DG.,. Mansuy IM, Osman M, T. Moallem M and Kandel ER. 1998. "Genetic and pharmacological evidence for a novel, intermediate phase of long-term potentiation suppressed by calcineurin." Cell 92(1): 25-37.
Mansuy IM, Winder DG, Moallem TM, Osman M, Mayford M, Hawkins RD, Kandel ER. 1998. Inducible and reversible gene expression with the rtTA system for the study of memory. Neuron 21:257-265.
Zoladz PR, Park CR, Halonen JD, Salim S, Alzoubi KH, Srivareerat M, Fleshner M, Alkadhi KA, Diamond DM. 2012. Differential expression of molecular markers of synaptic plasticity in the hippocampus, prefrontal cortex, and amygdala in response to spatial learning, predator exposure, and stressinduced amnesia. Hippocampus 22 (3):577–589
Takase K, Yamamoto Y, Yagami T. 2012. Maternal deprivation in the middle of a stress hyporesponsive period decreases hippocampal calcineurin expression and causes abnormal social and cognitive behaviours in adult male Wistar rats: relevance to negative symptoms of schizophrenia. Behav Brain Res 232:306–315
Gerges, NZ, Aleisa, AM; Schwarz LA and Alkadhi KA. 2003. Chronic psychosocial stress decreases calcineurin in the dentate gyrus: a possible mechanism for preservation of early LTP. Neuroscience 117:869-874.
Gong CX, Singh TJ, Grundke-Iqbal I, Iqbal K. 1994. Alzheimer'sdisease abnormally phosphorylated tau is dephosphorylated by protein phosphatase-2B (calcineurin). J Neurochem. 62(2):803-806.
Berridge MJ. 2010. Calcium hypothesis of Alzheimer's disease. Pflugers Arch 459: 441-449.
Hata R, Masumura M, Akatsu H, Li F, Fujita H, Nagai Y, et al. 2001. Up-regulation of calcineurin Abeta mRNA in the Alzheimer's disease brain: assessment by cDNA microarray. Biochem Biophys Res Commun 284: 310-316.
Taglialatela G, Hogan D, Zhang WR, Dineley KT. 2009. Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition. Behav Brain Res 200(1):95–99
Mbebi C, See V, Mercken L, Pradier L, Muller U, Loeffler JP. 2002. Amyloid precursor protein family-induced neuronal death is mediated by impairment of the neuroprotective calcium/calmodulin protein kinase IV-dependent signaling pathway. J Biol Chem 277: 20979-20990
Norris, C. M., Kadish, I., Blalock, E. M., Chen, K. C., Thibault, V., Porter, N. M., et al. 2005. Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer’s models. The Journal of Neuroscience, 25, 4649–4658.
Datson NA, Speksnijder N, Mayer JL, Steenbergen PJ, Korobko O, Goeman J, de Kloet ER, Joe¨ls M, Lucassen PJ. 2012. The transcriptional response to chronic stress and glucocorticoid receptor blockade in the hippocampal dentate gyrus. Hippocampus 22(2):359–371
Alberini CM. 2009. Transcription factors in long-term memory and synaptic plasticity. Physiol Rev 89(1):121-145.
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.
Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P. 2005. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8:1051-1058.
Lonze BE, Ginty DD. 2002. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35:605-623.
Ghosh A, Carnahan J, Greenberg ME. 1994. Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263:1618-1623.
Lindholm D, Carroll P, Tzimagiogis G, Thoenen H. 1996. Jul Autocrine-paracrine regulation of hippocampal neuron survival by IGF-1 and the neurotrophins BDNF, NT-3 and NT-4. Eur J Neurosci.;8(7):1452-1460.
Knusel B, Beck KD, Winslow JW, Rosenthal A, Burton LE, Widmer HR, Nikolics K, Hefti F. 1992. Brain-derived neurotrophic factor administration protects basal forebrain cholinergic but not nigral dopaminergic neurons from degenerative changes after axotomy in the adult rat brain. J Neurosci 12:4391-4402.
Bramham CR, Messaoudi E. 2005. BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76:99-125.
Soule J, Messaoudi E, Bramham CR. 2006. Brain-derived neurotrophic factor and control of synaptic consolidation in the adult brain. Biochem Soc Trans 34:600-604.
Huang EJ, Reichardt LF. 2001. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677-736.
Yamada K, Mizuno M, Nabeshima T. 2002. Role for brain-derived neurotrophic factor in learning and memory. Life Sci 70:735-744.
Lee KW, Kim JB, Seo JS, Kim TK, Im JY, Baek IS, Kim KS, Lee JK, Han PL. 2009. Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress. J Neurochem 108:165-175.
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.
Alkadhi KA. 2023. A rat model of pre-clinical Alzheimer’s disease. Chapter 4 in Handbook of Animal Models in Neurological Disorders. Martin, Patel and Preedy (Eds). Elsevier Inc.
Tong L, Balazs R, Thornton PL, Cotman CW. 2004. Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. J Neurosci. 24(30):6799-6809.
Querfurth, H. W., & LaFerla, F. M. 2010. Alzheimer’s disease. The New England Journal of Medicine, 362, 329–344.
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
Zhao D, Watson JB, Xie CW. 2004. Amyloid beta prevents activation of calcium/calmodulin-dependent protein kinase II and AMPA receptor phosphorylation during hippocampal long-term potentiation. J Neurophysiol 92:2853-2858
Conrad CD, Lupien SJ, McEwen BS. 1999. Support for a bimodal role for type II adrenal steroid receptors in spatial memory. Neurobiol Learn Mem 72:39-46
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
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.
Liang Z, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. 2007. Down-regulation of cAMP-dependent protein kinase by over-activated calpain in Alzheimer disease brain. J Neurochem 103:2462-2470.
Liu F, Grundke-Iqbal I, Iqbal K, Oda Y, Tomizawa K, Gong CX. 2005. Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. J Biol Chem 280:37755-37762
Durany N, Michel T, Kurt J, Cruz-Sanchez FF, Cervas-Navarro J, Riederer P. 2000. Brain-derived neurotrophic factor and neurotrophin-3 levels in Alzheimer's disease brains. Int J Dev Neurosci 18:807-813.
Lindvall O, Ernfors P, Bengzon J, Kokaia Z, Smith ML, Siesjo BK, Persson H.1992. Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma. Proc Natl Acad Sci U S A 89:648-652.
Zuccato C, Cattaneo E. 2009. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 5(6):311-322
Tang Y, Yamada K, Kanou Y, Miyazaki T, Xiong X, Kambe F, Murata Y, Seo H, Nabeshima T. 2000. Spatiotemporal expression of BDNF in the hippocampus induced by the continuous intracerebroventricular infusion of beta-amyloid in rats. Brain Res Mol Brain Res 80:188-197.
Hellstrom-Lindahl E, Court J, Keverne J, Svedberg M, Lee M, Marutle A, Thomas A, Perry E, Bednar I, Nordberg A. 2004. Nicotine reduces A beta in the brain and cerebral vessels of APPsw mice. Eur J Neurosci 19:2703-2710.
Catania C, Sotiropoulos I, Silva R, Onofri C, Breen KC, Sousa N, Almeida OF. 2009. The amyloidogenic potential and behavioral correlates of stress. Mol Psychiatry 14:95–105
How to Cite
Copyright (c) 2023 Journal of Contemporary Medical Sciences
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.