Accessible Requires Authentication Published by De Gruyter August 29, 2014

Chronic stress as a risk factor for Alzheimer’s disease

Alberto Machado, Antonio J. Herrera, Rocío M. de Pablos, Ana María Espinosa-Oliva, Manuel Sarmiento, Antonio Ayala, José Luis Venero, Martiniano Santiago, Ruth F. Villarán, María José Delgado-Cortés, Sandro Argüelles and Josefina Cano


This review aims to point out that chronic stress is able to accelerate the appearance of Alzheimer’s disease (AD), proposing the former as a risk factor for the latter. Firstly, in the introduction we describe some human epidemiological studies pointing out the possibility that chronic stress could increase the incidence, or the rate of appearance of AD. Afterwards, we try to justify these epidemiological results with some experimental data. We have reviewed the experiments studying the effect of various stressors on different features in AD animal models. Moreover, we also point out the data obtained on the effect of chronic stress on some processes that are known to be involved in AD, such as inflammation and glucose metabolism. Later, we relate some of the processes known to be involved in aging and AD, such as accumulation of β-amyloid, TAU hyperphosphorylation, oxidative stress and impairement of mitochondrial function, emphasizing how they are affected by chronic stress/glucocorticoids and comparing with the description made for these processes in AD. All these data support the idea that chronic stress could be considered a risk factor for AD.

Corresponding author: Rocío M. de Pablos, Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, c/o Profesor García González, 2, E-41012 Sevilla, Spain, e-mail:
aPresent address: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford OX3 7LJ, UKbPresent address: National Institutes of Health, National Institute on Aging, Biomedical Research Center, Laboratory of Neurosciences, 251 Bayview Boulevard, Baltimore, MD 21224, USAcDeceased.


This work was supported by grant SAF-2012-39029 from the Spanish Ministry of Economy and Competitiveness and P10-CTS-6494 (Proyecto de Excelencia of Junta de Andalucia).

Conflicts of interest statement: The authors declare that they have no conflicts of interest.


Abercrombie, H.C., Jahn, A.L., Davidson, R.J., Kern, S., Kirschbaum, C., and Halverson, J. (2011). Cortisol’s effects on hippocampal activation in depressed patients are related to alterations in memory formation. J. Psychiatr. Res. 45, 15–23. Search in Google Scholar

Abrahám, I., Harkany, T., Horvath, K.M., Veenema, A.H., Penke, B., Nyakas, C., and Luiten P.G. (2000). Chronic corticosterone administration dose-dependently modulates Aβ(1-42)- and NMDA-induced neurodegeneration in rat magnocellular nucleus basalis. J. Neuroendocrinol. 12, 486–494. Search in Google Scholar

Abramov, A.Y. and Duchen, M.R. (2005). The role of an astrocytic NADPH oxidase in the neurotoxicity of amyloid β peptides. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 360, 2309–2314. Search in Google Scholar

Adachi, N., Chen, J., Liu, K., Tsubota, S., and Arai, T. (1998). Dexamethasone aggravates ischemia induced neuronal damage by facilitating the onset of anoxic depolarization and the increase in the intracellular Ca2+ concentration in gerbil hippocampus. J. Cereb. Blood Flow Metab. 18, 274–280. Search in Google Scholar

Aisa, B., Tordera, R., Lasheras, B., Del Río, J., and Ramírez, M.J. (2007). Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats. Psychoneuroendocrinology 32, 256–266. Search in Google Scholar

Amatruda, J.M., Livingston, J.N., and Lockwood, D.H. (1985). Cellular mechanisms in selected states of insulin resistance: human obesity, glucocorticoid excess, and chronic renal failure. Diabetes Metab. Rev. 1, 293–317. Search in Google Scholar

Argüelles, S., Herrera, A.J., Carreño-Müller, E., de Pablos, R.M., Villarán, R.F., Espinosa-Oliva, A.M., Machado, A., and Cano, J. (2010). Degeneration of dopaminergic neurons induced by thrombin injection in the substantia nigra of the rat is enhanced by dexamethasone: role of monoamine oxidase enzyme. Neurotoxicology 31, 55–66. Search in Google Scholar

Atamna, H. and Frey, W.H. 2nd. (2007). Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease. Mitochondrion 7, 297–310. Search in Google Scholar

Atif, F., Yousuf, S., and Agrawal, S.K. (2008). Restraint stress-induced oxidative damage and its amelioration with selenium. Eur. J. Pharmacol. 600, 59–63. Search in Google Scholar

Baglietto-Vargas, D., Medeiros, R., Martinez-Coria, H., LaFerla, F.M., and Green, K.N. (2013). Mifepristone alters amyloid precursor protein processing to preclude amyloid beta and also reduces tau pathology. Biol Psychiatry 74, 357–366. Search in Google Scholar

Baker, A.F., Briehl, M.M., Dorr, R., and Powis, P. (1996). Decreased antioxidant defence and increased oxidant stress during dexamethasone-induced apoptosis: bcl-2 prevents the loss of antioxidant enzyme activity. Cell Death Diff. 3, 207–213. Search in Google Scholar

Behl, C., Trapp, T., Skutella, T., and Holsboer, F. (1997). Protection against oxidative stress-induced neuronal cell death – a novel role for RU486. Eur. J. Neurosci. 9, 912–920. Search in Google Scholar

Belanoff, J.K., Gross, K., Yager, A., and Schatzberg, A.F. (2001). Corticosteroids and cognition. J. Psychiatr. Res. 35, 127–145. Search in Google Scholar

Berent, S., Giordani, B., Foster, N., Minoshima, S., Lajiness-O’Neill, R., Koeppe, R., and Kuhl, D.E. (1999). Neuropsychological function and cerebral glucose utilization in isolated memory impairment and Alzheimer’s disease. J. Psychiatr. Res. 33, 7–16. Search in Google Scholar

Bertram, L. and Tanzi, R.E. (2008). Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nature Rev. Neurosci. 9, 768–778. Search in Google Scholar

Bishop, N.A., Lu, T., and Yankner, B.A. (2010). Neural mechanisms of ageing and cognitive decline. Nature 464, 529– 535. Search in Google Scholar

Blasko, I., Marx, F., Steiner, E., Hartmann, T., and Grubeck-Loebenstein, B. (1999). TNFalpha plus IFNgamma induce the production of Alzheimer β-amyloid peptides and decrease the secretion of APPs. FASEB J. 13, 63–68. Search in Google Scholar

Bons, N., Jallageas, V., Mestre-Francés, N., Silhol, S., Petter, A., and Delacourte, A. (1995). Microcebus murinus, a convenient laboratory animal model for the study of Alzheimer’s disease. Alzheimer’s Res. 1, 83–87. Search in Google Scholar

Braak, H., Braak, E., and Strothjohann, M. (1994). Abnormally phosphorylated tau protein related to the formation of neurofibrillary tangles and neuropil threads in the cerebral cortex of sheep and goat. Neurosci. Lett. 171, 1–4. Search in Google Scholar

Briones, T.L. and Darwish, H. (2014). Decrease in age-related tau hyperphosphorylation and cognitive improvement following vitamin D supplementation are associated with modulation of brain energy metabolism and redox state. Neuroscience 262, 143–55. Search in Google Scholar

Brunetti, A., Fulham, M.J., Aloj, L., De Souza, B., Nieman, L., Oldfield, E.H., and Di Chiro, G. (1998). Decreased brain glucose utilization in patients with Cushing’s disease. J. Nucl. Med. 39, 786–790. Search in Google Scholar

Burnes, D.P. and Burnette, D.J. (2013). Broadening the etiological discourse on Alzheimer’s disease to include trauma and posttraumatic stress disorder as psychosocial risk factors. Aging Stud. 27, 218–224. Search in Google Scholar

Butterfield, D.A., Drake, J., Pocernich, C., and Castegna, A. (2001). Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid β-peptide. Trends Mol. Med. 7, 548–554. Search in Google Scholar

Buxbaum, J.D., Oishi, M., Chen, H.I., Pinkas-Kramarski, R., Jaffe, E.A., Gandy, S.E., and Greengard, P. (1992). Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer β/A4 amyloid protein precursor. Proc. Natl. Acad. Sci. USA 89, 10075–10078. Search in Google Scholar

Calingasan, N.Y., Uchida, K., and Gibson, G.E. (1999). Protein-bound acrolein: a novel marker of oxidative stress in Alzheimer’s disease, J. Neurochem. 72, 751–756. Search in Google Scholar

Cao, K., Chen-Plotkin, A.S., Plotkin, J.B., and Wang, L-S. (2010). Age-correlated gene expression in normal and neurodegenerative human brain tissues. PLoS One 5, pii:e13098. Search in Google Scholar

Cardoso, S.M., Santana, I., Swerdlow, R.H., and Oliveira, C.R. (2004). Mitochondria dysfunction of Alzheimer’s disease cybrids enhances Aβ toxicity. J. Neurochem. 89, 1417–1426. Search in Google Scholar

Carlo, P., Violani, E., Del Rio, M., Olasmaa, M., Santagati, S., Maggi, A., and Picotti, G.B. (1996). Monoamine oxidase B expression is selectively regulated by dexamethasone in cultured rat astrocytes. Brain Res. 711, 175–183. Search in Google Scholar

Carreño-Müller, E., Herrera, A.J., de Pablos, R.M., Tomás-Camardiel, M., Venero, J.L., Cano, J., and Machado, A. (2003). Thrombin induces in vivo degeneration of nigral dopaminergic neurones along with the activation of microglia. J. Neurochem. 84, 1201–1214. Search in Google Scholar

Carroll, J.C., Iba, M., Bangasser, D.A., Valentino, R.J., James, M.J., Brunden, K.R., Lee, V.M., and Trojanowski, J.Q. (2011). Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy. J Neurosci. 31, 14436–14449. Search in Google Scholar

Castaño, A., Herrera, A.J., Cano, J., and Machado, A. (1998). Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system. J. Neurochem. 70, 1584–1592. Search in Google Scholar

Castaño, A., Herrera, A.J., Cano, J., and Machado, A. (2002). The degenerative effect of a single intranigral injection of LPS on the dopaminergic system is prevented by dexamethasone, and not mimicked by rh-TNF-α, IL-1β and IFN-γ. J. Neurochem. 81, 150–157. Search in Google Scholar

Catania, C., Sotiropoulos, I., Silva, R., Onofri, C., Breen, K.C., Sousa, N., and Almeida, O.F. (2009). The amyloidogenic potential and behavioral correlates of stress. Mol. Psychiatry 14, 95–105. Search in Google Scholar

Ceballos-Picot, I., Nicole, A., Clement, M., Bourre, J.M., and Sinet, P.M. (1992). Age-related changes in antioxidant enzymes and lipid peroxidation in brains of control and transgenic mice overexpressing copper-zinc superoxide dismutase, Mutat. Res. 275, 281–293. Search in Google Scholar

Coluccia, D., Wolf, O.T., Kollias, S., Roozendaal, B., Forster, A., and de Quervain D.J. (2008). Glucocorticoid therapy-induced memory deficits: acute versus chronic effects. J. Neurosci. 28, 3474–3478. Search in Google Scholar

Copeland, J.M., Cho, J., Lo, T. Jr., Hur, J.H., Bahadorani, S., Arabyan, T., Rabie, J., Soh, J., and Walker, D.W. (2009). Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr. Biol. 19, 1591–1598. Search in Google Scholar

Cork, L.C., Powers, R.E., Selkoe, D.J., Davies, P., Geyer, J.J., and Price, D.L. (1988). Neurofibrillary tangles and senile plaques in aged bears. J. Neuropathol. Exp. Neurol. 47, 629–641. Search in Google Scholar

Croisier, E., Moran, L.B., Dexter, D.T., Pearce, R.K., and Graeber, M.B. (2005). Microglial inflammation in the parkinsonian substantia nigra: relationship to α-synuclein deposition. J. Neuroinflammation. 3, 2–14. Search in Google Scholar

Csernansky, J.G., Dong, H., Fagan, A.M., Wang, L., Xiong, C., Holtzman, D.M., and Morris, J.C. (2006). Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am. J. Psychiatry 163, 2164–2169. Search in Google Scholar

Cuadrado-Tejedor, M., Cabodevilla, J.F., Zamarbide, M., Gómez-Isla, T., Franco, R. and Perez-Mediavilla, A. (2013). Age-related mitochondrial alterations without neuronal loss in the hippocampus of a transgenic model of Alzheimer’s disease. Curr Alzheimer Res. 10, 390–405. Search in Google Scholar

Cui, B., Zhu, L. She, X., Wu, M., Ma, Q., Wang, T., Zhang, N., Xu, C., Chen, X., An, G., et al. (2012). Chronic noise exposure causes persistence of tau hyperphosphorylation and formation of NFT tau in the rat hippocampus and prefrontal cortex. Exp Neurol. 238, 122–129. Search in Google Scholar

de Leon, M.J., Ferris, S.H., George, A.E., Reisberg, B., Christman, D.R., Kricheff, I.I., and Wolf, A.P. (1983a). Computed tomography and positron emission transaxial tomography evaluations of normal aging and Alzheimer’s disease. J. Cereb. Blood Flow Metab. 3, 391–394. Search in Google Scholar

de Leon, M.J., Ferris, S.H., George, A.E., Christman, D.R., Fowler, J.S., Gentes, C., Reisberg, B., Gee, B., Emmerich, M., Yonekura, Y., et al. (1983b). Positron emission tomographic studies of aging and Alzheimer disease. AJNR Am. J. Neuroradiol. 4, 568–571. Search in Google Scholar

de Leon, M.J., McRae, T., Rusinek, H., Convit, A., De Santi, S., Tarshish, C., Golomb, J., Volkow, N., Daisley, K., Orentreich, N., et al. (1997). Cortisol reduces hippocampal glucose metabolism in normal elderly, but not in Alzheimer’s disease. J. Clin. Endocrinol. Metab. 82, 3251–3259. Search in Google Scholar

de Pablos, R.M., Herrera, A.J., Villarán, R.F., Cano, J., and Machado, A. (2005). Dopamine-dependent neurotoxicity of lipopolysaccharide in substantia nigra. FASEB J. 19, 407–409. Search in Google Scholar

de Pablos, R.M., Villarán, R.F., Argüelles, S., Herrera, A.J., Venero, J.L., Ayala, A., Cano, J., and Machado, A. (2006). Stress increases vulnerability to inflammation in the rat prefrontal cortex. J. Neurosci. 26, 5709–5719. Search in Google Scholar

de Pablos, R.M., Herrera, A.J., Espinosa-Oliva, A.M., Sarmiento, M., Muñoz, M.F., Machado, A., and Venero, J.L. (2014). Chronic stress enhances microglia activation and exacerbates death of nigral dopaminergic neurons under conditions of inflammation. J Neuroinflammation 11, 34. Search in Google Scholar

de Quervain, D.J., Poirier, R., Wollmer, M.A., Grimaldi, L.M., Tsolaki, M., Streffer, J.R., Hock, C., Nitsch, R.M., Mohajeri, M.H., and Papassotiropoulos, A. (2004). Glucocorticoid-related genetic susceptibility for Alzheimer’s disease. Hum. Mol. Genet. 13, 47–52. Search in Google Scholar

Desgranges, B., Baron, J.C., de la Sayette, V., Petit-Taboué, M.C., Benali, K., Landeau, B., Lechevalier, B., and Eustache, F. (1998). The neural substrate of memory systems impairment in Alzheimer’s disease. A PET study of resting brain glucose utilization. Brain 121, 611–631. Search in Google Scholar

Dhikav, V. and Anand, K.S. (2007). Glucocorticoids may initiate Alzheimer’s disease: a potential therapeutic role for mifepristone (RU-486). Med. Hypotheses 68, 1088–1092. Search in Google Scholar

Dodart, J.C., Mathis, C., Bales, K.R., Paul, S.M., and Ungerer, A. (1999). Early regional cerebral glucose hypometabolism in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Neurosci. Lett. 277, 49–52. Search in Google Scholar

Dong, H., Goico, B., Martin, M., Csernansky, C.A., Bertchume, A., and Csernansky, J.G. (2004). Modulation of hipocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience 127, 601–609. Search in Google Scholar

Dong, H., Yuede, C.M., Yoo, H.S., Martin, M.V., Deal, C., Mace, A.G., and Csernansky, J.G. (2008). Corticosterone and related receptor expression are associated with increased β-amyloid plaques in isolated Tg2576 mice. Neuroscience 155, 154–163. Search in Google Scholar

Du, J., Wang, Y., Hunter, R., Wei, Y., Blumenthal, R., Falke, C., Khairova, R., Zhou, R., Yuan, P., Machado-Vieira, R., et al. (2009). Dynamic regulation of mitochondrial function by glucocorticoids. Proc. Natl. Acad. Sci. USA 106, 3543–3548. Search in Google Scholar

Dunn, A.J., Wang, J., and Ando, T. (1999). Effects of cytokines on cerebral neurotransmission. Comparison with the effects of stress. Adv. Exp. Med. Biol. 461, 117–127. Search in Google Scholar

Edenfield, T.M. and Saeed, S.A. (2012). An update on mindfulness meditation as a self-help treatment for anxiety and depression. Psychol. Res. Behav. Manag. 5, 131–141. Search in Google Scholar

Endo, Y., Nishimura, J., and Kimura, F. (1994). Adrenalectomy increases local cerebral blood flow in the rat hippocampus. Pflüger’s Arch. 426, 83–88. Search in Google Scholar

Epel, E.S., Blackburn, E.H., Lin, J., Dhabhar, F.S., Adler, N.E., Morrow, J.D., and Cawthon, R.M. (2004). Accelerated telomere shortening in response to life stress. Proc. Natl. Acad. Sci. USA 101, 17312–17315. Search in Google Scholar

Espinosa-Oliva, A.M., de Pablos, R.M., Villarán, R.F., Argüelles, S., Venero, J.L., Machado, A., and Cano, J. (2011). Stress is critical for LPS-induced activation of microglia and damage in the rat hippocampus. Neurobiol. Aging 32, 85–102. Search in Google Scholar

Filipcik, P., Novak, P., Mravec, B., Ondicova, K., Krajciova, G., Novak, M., and Kvetnansky, R. (2012). Tau protein phosphorylation in diverse brain areas of normal and CRH deficient mice: up-regulation by stress. Cell Mol. Neurobiol. 32, 837–845. Search in Google Scholar

Fontella, F.U., Siqueira, I.R., Vasconcellos, A.P., Tabajara, A.S., Netto, C.A., and Dalmaz, C. (2005). Repeated restraint stress induces oxidative damage in rat hippocampus. Neurochem. Res. 30, 105–111. Search in Google Scholar

Freo, U., Holloway, H.W., Kalogeras, K., Rapoport, S.I., and Soncrant, T.T. (1992). Adrenalectomy or metyrapone-pretreatment abolishes cerebral metabolic responses to the serotonin agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in the hippocampus. Brain Res. 586, 256–264. Search in Google Scholar

Fulham, M.J., Brunetti, A., Aloj, L., Raman, R., Dwyer, A.J., and Di Chiro, G. (1995). Decreased cerebral glucose metabolism in patients with brain tumors: an effect of corticosteroids. J. Neurosurg. 83, 657–664. Search in Google Scholar

Fuster-Matanzo, A., Llorens-Martin, M., Jurado-Arjona, J., Avila, J., and Hernandez, F. (2012). Tau protein and adult hippocampal neurogenesis. Front. Neurosci. 6, 104. Search in Google Scholar

Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., et al. (1995). Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527. Search in Google Scholar

Ghoumari, A.M., Dusart, I., El-Etr, M., Tronche, F., Sotelo, C., Schumacher, M., and Baulieu, E.E. (2003). Mifepristone (RU486) protects Purkinje cells from cell death in organotypic slice cultures of postnatal rat and mouse cerebellum. Proc. Natl. Acad. Sci. USA 100, 7953–7958. Search in Google Scholar

Gibson, G.E., Ratan, R.R., and Beal, M.F. (2008). Mitochondria and oxidative stress in neurodegenerative disorders. Preface. Ann. NY Acad. Sci. 1147, xi-xii. Search in Google Scholar

Gillardon, F., Rist, W., Kussmaul, L., Vogel, J., Berg, M., Danzer, K., Kraut, N., and Hengerer, B. (2007). Proteomics 7, 605–616. Search in Google Scholar

Goodman, Y., Bruce, A.J., Cheng, B., and Mattson, M.P. (1996). Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid β-peptide toxicity in hippocampal neurons. J. Neurochem. 66, 1836–1844. Search in Google Scholar

Goosens, K.A. and Sapolsky, R.M. (2007). Stress and Glucocorticoid Contributions to Normal and Pathological Aging, in Brain Aging: Models, Methods, and Mechanisms.D. R. Riddle ed., chapter 13. (CRC Press, Boca Raton). Search in Google Scholar

Gotz, J., Xia, D., Leinenga, G., Chew, Y.L., and Nicholas, H. (2013). What renders TAU toxic. Front. Neurol. 4, 72. Search in Google Scholar

Green, K.N., Billings, L.M., Roozendaal, B., McGaugh, J.L., and LaFerla, F.M. (2006). Glucocorticoids increase amyloid-β and tau pathology in a mouse model of Alzheimer’s disease. J. Neurosci. 26, 9047–9056. Search in Google Scholar

Guo, J.T., Yu, J., Grass, D., de Beer, F.C., and Kindy, M.S. (2002). Inflammation-dependent cerebral deposition of serum amyloid a protein in a mouse model of amyloidosis. J. Neurosci. 22, 5900–5909. Search in Google Scholar

Harris-White, M.E., Chu, T., Miller, S.A., Simmons, M., Teter, B., Nash, D., Cole, G.M., and Frautschy, S.A. (2001). Estrogen (E2) and glucocorticoid (Gc) effects on microglia and Aβ clearance in vitro and in vivo. Neurochem. Int. 39, 435–448. Search in Google Scholar

Härtig, W., Klein, C., Brauer, K.,. Schüppel, K.F, Arendt, T., Brückner, G., and Bigl, V. (2000). Abnormally phosphorylated protein tau in the cortex of aged individuals of various mammalian orders. Acta Neuropathol. 100, 305–312. Search in Google Scholar

Härtig, W., Klein, C., Brauer, K., Schüppel, K.F., Arendt, T., Bigl, V., and Brückner, G. (2001). Hyperphosphorylated protein tau is restricted to neurons devoid of perineuronal nets in the cortex of aged bison. Neurobiol. Aging, 22, 25–33. Search in Google Scholar

Härtig, W., Oklejewicz, M., Strijkstra, A.M, Boerema, A.S., Stieler, J., and Arendt, T. (2005). Phosphorylation of the tau protein sequence 199-205 in the hippocampal CA3 region of Syrian hamsters in adulthood and during aging. Brain Res. 1056, 100–104. Search in Google Scholar

Hashiguchi, M. and Hashiguchi, Y. (2013). Kinase-kinase interaction and modulation of tau phosphorylation. Int. Rev. Cell. Mol. Biol. 300, 121–160. Search in Google Scholar

Hebert, L.E., Scherr, P.A., Bienias, J.L., Bennett, D.A., and Evans, D.A. (2003). Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch. Neurol. 60, 1119–1122. Search in Google Scholar

Hensley, K., Carney, J.M., Mattson, M.P., Aksenova, M., Harris, M., Wu, J.F., Floyd, R.A., and Butterfield, D.A. (1994). A model for β-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc. Natl. Acad. Sci. USA 91, 3270–3274. Search in Google Scholar

Hernández-Romero, M.C., Argüelles, S., Villarán, R.F., de Pablos, R.M., Delgado-Cortés, M.J., Santiago, M., Herrera, A.J., Cano, J., and Machado, A. (2008). Simvastatin prevents the inflammatory process and the dopaminergic degeneration induced by the intranigral injection of lipopolysaccharide. J. Neurochem. 105, 445–459. Search in Google Scholar

Herrera, A.J., Castaño, A., Venero, J.L., Cano, J., and Machado, A. (2000). The single intranigral injection of LPS as a new model for studying the selective effects of inflammatory reactions on dopaminergic system. Neurobiol. Dis. 7, 429–447. Search in Google Scholar

Herrera, A. J., Tomás-Camardiel, M., Venero, J.L., Cano, J., and Machado, A. (2005). Inflammatory process as a determinant factor for the degeneration of substantia nigra dopaminergic neurons. J. Neural. Transm. 112, 111–119. Search in Google Scholar

Herrera, A.J., de Pablos, R.M., Carreño-Müller, E., Villarán, R.F., Venero, J.L., Tomás-Camardiel, M., Cano, J., and Machado, A. (2008). The intrastriatal injection of thrombin in rat induced a retrograde apoptotic degeneration of nigral dopaminergic neurons through synaptic elimination. J. Neurochem. 105, 750–762. Search in Google Scholar

Hirai, K., Aliev, G., Nunomura, A., Fujioka, H., Russell, R.L., Atwood, C.S., Johnson, A.B., Kress, Y., Vinters, H.V., Tabaton, M., et al. (2001). Mitochondrial abnormalities in Alzheimer’s disease. J. Neurosci. 21, 3017–3023. Search in Google Scholar

Hirose, Y., Imai, Y., Nakajima, K., Takemoto, N., Toya, S., and Kohsaka, S. (1994). Glial conditioned medium alters the expression of amyloid precursor protein in SH-SY5Y neuroblastoma cells. Biochem. Biophys. Res. Commun. 198, 504–509. Search in Google Scholar

Horner, H.C., Packan, D.R., and Sapolsky, R.M. (1990). Glucocorticoids inhibit glucose transport in cultured hippocampal neurons and glia. Neuroendocrinology 52, 57–64. Search in Google Scholar

Ibáñez, V., Pietrini, P., Alexander, G.E., Furey, M.L., Teichberg, D., Rajapakse, J.C., Rapoport, S.I., Schapiro, M.B., and Horwitz, B. (1998). Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer’s disease. Neurology 50, 1585–1593. Search in Google Scholar

Iqbal, K. and Grundke-Iqbal, I. (2008). Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention. J. Cell Mol. Med. 12, 38–55. Search in Google Scholar

Iuchi, T., Akaike, M., Mitsui, T., Ohshima, Y., Shintani, Y., Azuma, H., and Matsumoto, T. (2003). Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. Circ. Res. 92, 81–87. Search in Google Scholar

Jang, Y.C. and Remmen, V.H. (2009). The mitochondrial theory of aging: insight from transgenic and knockout mouse models. Exp. Gerontol. 44, 256–260. Search in Google Scholar

Jeong, Y.H., Park, C.H., Yoo, J., Shin, K.Y., Ahn, S.M., Kim, H.S., Lee, S.H., Emson, P.C., and Suh, Y.H. (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. Search in Google Scholar

Johansson, L., Guo, X., Waern, M., Ostling, S., Gustafson, D., Bengtsson, C., and Skoog, I. (2010). Midlife psychological stress and risk of dementia: a 35-year longitudinal population study. Brain 133, 2217–2224. Search in Google Scholar

Jorm, A.F. and Jolley, D. (1998). The incidence of dementia: a meta-analysis. Neurology 51, 728–733. Search in Google Scholar

Kadekaro, M., Ito, M., and Gross, P.M. (1988). Local cerebral glucose utilization is increased in acutely adrenalectomized rats. Neuroendocrinology 47, 329–334. Search in Google Scholar

Kang, J.E., Cirrito, J.R., Dong, H., Csernansky, J.G., and Holtzman, D.M. (2007). Acute stress increases interstitial fluid amyloid-β via corticotropin-releasing factor and neuronal activity. Proc. Natl. Acad. Sci. USA 104, 10673–10678. Search in Google Scholar

Kashif, S.M., Zaidi, R., Al-Qirim, T.M, Hoda, M.N., and Banu, N. (2003). Modulation of restraint stress induced oxidative changes in rats by antioxidant vitamins. J. Nutrition Biochem. 14, 633–636. Search in Google Scholar

Kennedy, A.M., Rossor, M.N., and Frackowiak, R.S. (1995). Positron emission tomography in familial Alzheimer disease. Alzheimer Dis. Assoc. Disord. 9, 17–20. Search in Google Scholar

Khan, S.M., Cassarino, D.S., Abramova, N.N., Keeney, P.M., Borland, M.K., Trimmer, P.A., Krebs, C.T., Bennett, J.C., Parks, J.K., Swerdlow, R.H., et al. (2000). Alzheimer’s disease cybrids replicate β-amyloid abnormalities through cell death pathways. Ann. Neurol. 48, 148–155. Search in Google Scholar

Kim, J.J., Foy, M.R., and Thompson, R.F. (1996). Behavioral stress modifies hippocampal plasticity through N-methyl-D-aspartate receptor activation. Proc. Natl. Acad. Sci. USA 93, 4750–4753. Search in Google Scholar

Kim, W.G., Mohney, R.P., Wilson, B., Jeohn, G.H., Liu, B., and Hong, J.S. (2000). Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J. Neurosci. 20, 6309–6316. Search in Google Scholar

Kimura, T., Yamashita, S., Fukuda, T., Park, J.M., Murayama, M., Mizoroki, T.,Yoshiike, Y., Sahara, N., and Takashima, A. (2007). Hyperphosphorylated TAU in parahippocampal cortex impairs place learning in aged mice expressing wild-type human TAU. EMBO J. 26, 5143–5152. Search in Google Scholar

Kitazawa, M., Oddo, S., Yamasaki, T.R., Green, K.N., and LaFerla, F.M. (2005). Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J. Neurosci. 25, 8843–8853. Search in Google Scholar

Kuhl, D.E., Metter, E.J., Riege, W.H., and Phelps, M.E. (1982). Effects of human aging on patterns of local cerebral glucose utilization determined by the [18F]fluorodeoxyglucose method. J. Cereb. Blood Flow Metab. 2, 163–171. Search in Google Scholar

Kulstad, J.J., McMillan, P.J., Leverenz, J.B., Cook, D.G., Green, P.S., Peskind, E.R., Wilkinson, C.W., Farris, W., Mehta, P.D., and Craft, S. (2005). Effects of chronic glucocorticoid administration on insulin-degrading enzyme and amyloid-β peptide in the aged macaque. J. Neuropathol. Exp. Neurol. 64, 139–146. Search in Google Scholar

Landfield, P.W., Blalock, E.M., Chen, K-C., and Porter, N.M. (2007). A new glucocorticoid hypothesis of brain aging: implications for Alzheimer’s disease. Curr. Alzheimer Res. 4, 205–212. Search in Google Scholar

Landgraf, R., Mitro, A., and Hess, J. (1978). Regional net uptake of 14C-glucose by rat brain under the influence of corticosterone. Endocrinol. Exp. 12, 119–129. Search in Google Scholar

Lee, K.W., Kim, J.B., Seo, J.S., Kim, T.K., Im, J.Y., Baek, I.S., Kim, K.S., Lee, J.K., and Han, P.L. (2009). Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress. J. Neurochem. 108, 165–175. Search in Google Scholar

Leza, J.C., Salas, E., Sawicki, G., Russell, J.C., and Radomski, M.W. (1998). The effects of stress on homeostasis in JCR-LA-cp rats: the role of nitric oxide. J. Pharmacol. Exp. Ther. 286, 1397–1403. Search in Google Scholar

Li, W.Z., Li, W.P., Yao, Y.Y., Zhang, W., Yin, Y.Y., Wu, G.C., and Gong, H.L. (2010). Glucocorticoids increase impairments in learning and memory due to elevated amyloid precursor protein expression and neuronal apoptosis in 12-month old mice. Eur. J. Pharmacol. 628, 108–115. Search in Google Scholar

Li, Z., Ma, L., Kulesskaya, N., Võikar, V., and Tian, L. (2014). Microglia are polarized to M1 type in high-anxiety inbred mice in response to lipopolysaccharide challenge. Brain Behav Immun 38, 237–248. Search in Google Scholar

Liang, W.S., Reiman, E.M., Valla, J., Dunckley, T., Beach, T.G., Grover, A., Niedzielko, T.L., Schneider, L.E., Mastroeni, D., Caselli, R., et al. (2008). Alzheimer’s disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc. Natl Acad. Sci. USA 105, 4441–4446. Search in Google Scholar

Liu, J., Wang, X., Shigenaga, M., Yeo, H., Mori, A., and Ames, B. (1996). Immobilization stress causes oxidative damage to lipid, protein, and DNA in the brain of rats. FASEB J. 10, 1532–1538. Search in Google Scholar

Loerch, P.M., Lu, T., Dakin, K.A., Vann, J.M., Isaacs, A., Geula, C., Wang, J., Pan, Y., Gabuzda, D.H., Li, C., et al. (2008). Evolution of the aging brain transcriptome and synaptic regulation. PLoS One 3, e3329. Search in Google Scholar

Lovell, M.A. and Markesbery, W.R. (2007). Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer’s disease. Nucleic Acids Res. 35, 7497–7504. Search in Google Scholar

Lu, T., Pan, Y., Kao, S.Y., Li, C., Kohane, I., Chan, J., and Yankner, B.A. (2004). Gene regulation and DNA damage in the ageing human brain. Nature 429, 883–891. Search in Google Scholar

MacPherson, A., Dinkel, K., and Sapolsky, R. (2005). Glucocorticoids worsen excitotoxin-induced expression of pro-inflammatory cytokines in hipocampal cultures. Exp. Neurol. 194, 376–383. Search in Google Scholar

Madrigal, J.L., Hurtado, O., Moro, M.A., Lizasoain, I., Lorenzo, P., Castrillo, A., Boscá, L., and Leza, J.C. (2002). The increase in TNF-α levels is implicated in NF-κB activation and inducible nitric oxide synthase expression in brain cortex after immobilization stress. Neuropsychopharmacology 26, 155–163. Search in Google Scholar

Madrigal, J.L, Garcia-Bueno, B., Caso, J.R., Perez-Nievas, B.G., and Leza, J.C. (2006). Stress-induced oxidative changes in brain. CNS Neurol. Disord. Drug Targets 5, 561–568. Search in Google Scholar

Magarinos, A.M. and McEwen, B.S. (1995). Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement ofglucocorticoid secretion and excitatory amino acid receptors. Neuroscience 69, 89–98. Search in Google Scholar

Mailliet, F., Qi, H., Rocher, C., Spedding, M., Svenningsson, P., and Jay, T.M. (2008). Protection of stress-induced impairment of hippocampal/prefrontal LTP through blockade of glucocorticoid receptors: implication of MEK signaling. Exp. Neurol. 211, 593–596. Search in Google Scholar

Mancuso, M., Orsucci, D., Siciliano, G., and Murri, L. (2008). Mitochondria, mitochondrial DNA and Alzheimer’s disease. What comes first? Curr. Alzheimer Res. 5, 457–468. Search in Google Scholar

Manoli, I., Le, H., Alesci, S., McFann, K.K., Su, Y.A., Kino, T., Chrousos, G.P., and Blackman, M.R. (2005). Monoamine oxidase-A is a major target gene for glucocorticoids in human skeletal muscle cells. FASEB J. 19, 1359–1361. Search in Google Scholar

Marcus, D.L. and Freedman, M.L. (1997). Decreased brain glucose metabolism in microvessels from patients with Alzheimer’s disease. Ann. NY Acad. Sci. 826, 248–253. Search in Google Scholar

Mark, R.J., Pang, Z., Geddes, J.W., Uchida, K., and Mattson, M.P. (1997). Amyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J. Neurosci. 17, 1046–1054. Search in Google Scholar

Masters, C.L. and Beyreuther, K. (1998). Alzheimer’s disease. Br. Med. J. 316, 446–448. Search in Google Scholar

Matsuoka, Y., Picciano, M., La Francois, J., and Duff, K. (2001). Fibrillar β-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimer’s disease. Neuroscience 104, 609–613. Search in Google Scholar

Mazanetz, M.P. and Fischer, P.M. (2007). Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat. Rev. Drug Discov. 6, 464–479. Search in Google Scholar

McClelland, D.C., Patel, V., Brown, D., and Kelner, S.P. Jr. (1991). The role of affiliative loss in the recruitment of helper cells among insulin-dependent diabetics. Behav Med. 17, 5–14. Search in Google Scholar

McCullers, D.L., Sullivan, P.G., Scheff, S.W., and Herman, J.P. (2002). Mifepristone protects CA1 hippocampal neurons following traumatic brain injury in rat. Neuroscience 109, 219–230. Search in Google Scholar

McGeer, E.G. and McGeer, P.L. (1998). The importance of inflammatory mechanisms in Alzheimer disease. Exp. Gerontol. 33, 371–378. Search in Google Scholar

Medina, M. and Avila, J. (2014). The role of extracellular Tau in the spreading of neurofibrillary pathology. Front Cell Neurosci. 8:113. Search in Google Scholar

Meguro, K., LeMestric, C., Landeau, B., Desgranges, B., Eustache, F., and Baron, J.C. (2001). Relations between hypometabolism in the posterior association neocortex and hippocampal atrophy in Alzheimer’s disease: a PET/MRI correlative study. J. Neurol. Neurosurg. Psychiatry 71, 315–321. Search in Google Scholar

Mehta, P.D., Mehta, S.P., Fedor, B., Patrick, B.A., Emmerling, M., and Dalton, A.J. (2003). Plasma amyloid protein 1–42 levels are increased in old Down syndrome but not in young Down syndrome. Neurosci. Lett. 342, 155–158. Search in Google Scholar

Meier-Ruge, W. and Bertoni-Freddari, C. (1996). The significance of glucose turnover in the brain in the pathogenetic mechanisms of Alzheimer’s disease. Rev. Neurosci. 7, 1–19. Search in Google Scholar

Meier-Ruge, W.A. and Bertoni-Freddari, C. (1997). Pathogenesis of decreased glucose turnover and oxidative phosphorylation in ischemic and trauma-induced dementia of the Alzheimer type. Ann. NY Acad.Sci. 826, 229–241. Search in Google Scholar

Mesulam, M.M. (1999). Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles. Neuron 24, 521–529. Search in Google Scholar

Miller, J.A., Oldham, M.C., and Geschwind, D.H. (2008). A systems level analysis of transcriptional changes in Alzheimer’s disease and normal aging. J. Neurosci. 28, 1410–1420. Search in Google Scholar

Moreira, P.I., Santos, M.S., and Oliveira, C.R. (2007). Alzheimer’s disease: a lesson from mitochondrial dysfunction. Antioxid. Redox Signal 9, 1621–1630. Search in Google Scholar

Morishima-Kawashima, M., Oshima, N., Ogata, H., Yamaguchi, H., Yoshimura, M., Sugihara, S., and Ihara, Y. (2000). Effect of apolipoprotein E allele e4 on the initial phase of amyloid β-protein accumulation in the human brain. Am. J. Pathol. 157, 2093–2099. Search in Google Scholar

Mosconi, L., Tsui, W.H., De Santi, S., Li, J., Rusinek, H., Convit, A., Li, Y., Boppana, M., and de Leon, M.J. (2005). Reduced hippocampal metabolism in MCI and AD: automated FDG-PET image analysis. Neurology 64, 1860–1867. Search in Google Scholar

Murphy, A.N., Bredesen, D.E., Cortopassi, G., Wang, E., and Fiskum, G. (1996). Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc. Natl. Acad. Sci. USA 93, 9893–9898. Search in Google Scholar

Nater, U.M., Skoluda, N., and Strahler, J. (2013). Biomarkers of stress in behavioural medicine. Curr Opin Psychiatry 26, 440–445. Search in Google Scholar

Nitta, A., Fukuta, T., Hasegawa, T., and Nabeshima, T. (1997). Continuous infusion of β-amyloid protein into the rat cerebral ventricle induces learning impairment and neuronal and morphological degeneration. Jpn. J. Pharmacol. 73, 51–57. Search in Google Scholar

Nunomura, A., Perry, G., Aliev, G., Hirai, K., Takeda, A., Balraj, E.K., Jones, P.K, Ghanbari, H., Wataya,T., Shimohama, S., et al. (2001). Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 759–767. Search in Google Scholar

Orzechowski, A., Grizard, J., Jank, M., Gajkowska, B., Lokociejewska, M., Zaron-Teperek, M., and Godlewski, M. (2002). Dexamethasone-mediated regulation of death and differentiation of muscle cells. Is hydrogen peroxide involved in the process? Reprod. Nutr. Dev. 42, 197–216. Search in Google Scholar

Orzechowski, A., Jank, M., Gajkowska, B., Sadkowski, T., Godlewski, M.M., and Ostaszewski, P. (2003). Delineation of signalling pathway leading to antioxidant-dependent inhibition of dexamethasone-mediated muscle cell death. J. Muscle Res. Cell Motil. 24, 33–53. Search in Google Scholar

Oshima, Y., Kuroda, Y., Kunishige, M., Matsumoto, T., and Mitsui, T. (2004). Oxidative stress-associated mitochondrial dysfunction in corticosteroid-treated muscle cells. Muscle Nerve 30, 49–54. Search in Google Scholar

Pace, T.W., Hu, F., and Miller, A.H. (2007). Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav. Immun. 21, 9–19. Search in Google Scholar

Pajović, S.B., Pejić, S., Stojiljković, V., Gavrilović, L., Dronjak, S., and Kanazir, D.T. (2006). Alterations in hippocampal antioxidant enzyme activities and sympatho-adrenomedullary system of rats in response to different stress models. Physiol. Res. 55, 453–460. Search in Google Scholar

Pamplona, R. and Barja, G. (2007). Highly resistant macromolecular components and low rate of generation of endogenous damage: two key traits of longevity. Ageing Res. Rev. 6, 189–210. Search in Google Scholar

Pecori Giraldi, F., Moro, M., and Cavagnini, F. (2003). Gender-related differences in the presentation and course of Cushing’s disease. J. Clin. Endocrinol. Metab. 88, 1554–1558. Search in Google Scholar

Pedersen, W.A. and Flynn, E.R. (2004). Insulin resistance contributes to aberrant stress responses in the Tg2576 mouse model of Alzheimer’s disease. Neurobiol. Dis. 17, 500–506. Search in Google Scholar

Pedersen, W.A., Culmsee, C., Ziegler, D., Herman, J.P., and Mattson, M.P. (1999). Aberrant stress response associated with severe hypoglycemia in a transgenic mouse model of Alzheimer’s disease. J. Mol. Neurosci. 13, 159–165. Search in Google Scholar

Pedersen, W.A., Wan, R., and Mattson, M.P. (2001). Impact of aging on stress-responsive neuroendocrine systems. Mech. Ageing Dev. 122, 963–983. Search in Google Scholar

Perani, D., Bressi, S., Cappa, S.F., Vallar, G., Alberoni, M., Grassi, F., Caltagirone, C., Cipolotti, L., Franceschi, M., Lenzi, G.L., and Fazio, F. (1993). Evidence of multiple memory systems in the human brain. A [18F]FDG PET metabolic study. Brain 116, 903–199. Search in Google Scholar

Petrie, E.C., Cross, D.J., Galasko, D., Schellenberg, G.D., Raskind, M.A., Peskind, E.R., and Minoshima, S. (2009). Preclinical evidence of Alzheimer changes: convergent cerebrospinal fluid biomarker and fluorodeoxyglucose positron emission tomography findings. Arch. Neurol. 66, 632–637. Search in Google Scholar

Piroli, G.G., Grillo, C.A., Reznikov, L.R., Adams, S., McEwen, B.S., Charron, M.J., and Reagan, L.P. (2007). Corticosterone impairs insulin-stimulated translocation of GLUT4 in the rat hippocampus. Neuroendocrinology 85, 71–80. Search in Google Scholar

Praticò, D., MY Lee, V., Trojanowski, J.Q., Rokach, J., and Fitzgerald, G.A. (1998). Increased F2-isoprostanes in Alzheimer’s disease: evidence for enhanced lipid peroxidation in vivo. FASEB J. 12, 1777–1783. Search in Google Scholar

Praticò, D., Uryu, K., Leight, S., Trojanoswki, J.Q., and Lee, V. M. (2001). Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J. Neurosci. 21,4183–4187. Search in Google Scholar

Qin, L., Wu, X., Block, M.L., Liu, Y., Breese, G.R., Hong, J.S., Knapp, D.J., and Crews, F.T. (2007). Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55, 453–462. Search in Google Scholar

Radak, Z., Sasvari, M., Nyakas, C., Kaneko, T., Ohno, H., and Goto, S. (2001). Single bout of exercise eliminates the immobilization-induced oxidative stress in rat brain. Neurochem. Int. 39, 33–38. Search in Google Scholar

Rapoport, S.I. (1999). In vivo PET imaging and postmortem studies suggest potentially reversible and irreversible stages of brain metabolic failure in Alzheimer’s disease. Eur. Arch. Psychiatry Clin. Neurosci. 249 Suppl 3, 46–55. Search in Google Scholar

Rea, S.L., Ventura, N., and Johnson, T.E. (2007). Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans. PLoS Biol. 5, e259. Search in Google Scholar

Reul, J.M. and de Kloet, E.R. (1985). Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117, 2505–2511. Search in Google Scholar

Ricci, S., Fuso, A., Ippoliti, F., and Businaro, R.J. (2012). Stress-induced cytokines and neuronal dysfunction in Alzheimer’s disease. Alzheimers Dis. 28, 11–24. Review. Search in Google Scholar

Rockenstein, E.M., McConlogue, L., Tan, H., Power, M., Masliah, E., and Mucke, L. (1995). Levels and alternative splicing of amyloid β protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer’s disease. J. Biol. Chem. 270, 28257–28267. Search in Google Scholar

Ros-Bernal, F., Hunot, S., Herrero, M.T., Parnadeau, S., Corvol, J.C., Lu, L., Alvarez-Fischer, D., Carrillo-de Sauvage, M.A., Saurini, F., Coussieu, C., et al. (2011). Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism. Proc. Natl. Acad. Sci. USA 108, 6632–6637. Search in Google Scholar

Rothman, S.M. and Mattson, M.P. (2010). Adverse stress, hippocampal networks, and Alzheimer’s disease. Neuromolecular Med. 12, 56–70. Search in Google Scholar

Rothman, S.M., Herdener, N., Camandola, S., Texel, S.J., Mughal, M.R., Cong, W.N., Martin, B., and Mattson, M.P. (2012). 3xTgAD mice exhibit altered behavior and elevated Aβ after chronic mild social stress. Neurobiol. Aging 33, 830.e1–12. Search in Google Scholar

Rowan, M.J., Klyubin, I., Cullen, W.K., and Anwyl, R. (2003). Synaptic plasticity in animal models of early Alzheimer’s disease. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 358, 821–828. Search in Google Scholar

Sahin, E. and Gumuslu, S. (2007a). Immobilization stress in rat tissues: alterations in protein oxidation, lipid peroxidation and antioxidant defense system. Comp. Biochem. Physiol. C. Toxicol. Pharmacol. 144, 342–347. Search in Google Scholar

Sahin, E. and Gumuslu, S. (2007b). Stress-dependent induction of protein oxidation, lipid peroxidation and anti-oxidants in peripheral tissues of rats: comparison of three stress models (immobilization, cold and immobilization-cold). Clin. Exp. Pharmacol. Physiol. 34, 425–431. Search in Google Scholar

Sanz, A., Pamplona, R., and Barja, G. (2006). Is the mitochondrial free radical theory of aging intact? Antioxid. Redox Signal 8, 582–599. Search in Google Scholar

Sapolsky, R.M., Krey, L.C., and McEwen, B.S. (1985). Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging. J. Neurosci. 5, 1222–1227. Search in Google Scholar

Sastre, M., Dewatcher, I., Landreth, G. E., Willson, T. M., Klockgether, T., van Leuven, F., and Heneka M. T. (2003). Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-γ agonists modulate immunostimulated processing of amyloid precursor protein through regulation of β-secretase. J. Neurosci. 23, 9796–9804. Search in Google Scholar

Schatzberg, A.F. and Lindley, S. (2008). Glucocorticoid antagonists in neuropsychotic disorders. Eur. J. Pharmacol. 583, 358–364. Search in Google Scholar

Schriner, S.E., Linford, N.J., Martin, G.M., Treuting, P., Ogburn, C.E., Emond, M., Coskun, P.E., Ladiges, W., Wolf, N., Van Remmen, H., et al. (2005). Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911. Search in Google Scholar

Schultz, C., Dehghani, F., Hubbard, G.B., Thal, D.R., Struckhoff, G., Braak, E., and Braak, H. (2000). Filamentous tau pathology in nerve cells, astrocytes, and oligodendrocytes of aged baboons. J. Neuropathol. Exp. Neurol. 59, 39–52. Search in Google Scholar

Selkoe, D.J. (2002). Alzheimer’s disease is a synaptic failure. Science 298, 789–791. Search in Google Scholar

Selvatici, R., Marani, L., Marino, S., and Siniscalchi, A. (2013) In vitro mitochondrial failure and oxidative stress mimic biochemical features of Alzheimer disease. Neurochem. Int. 63, 112–120. Search in Google Scholar

Shao, C., Xiong, S., Li, G.M., Gu, L., Mao, G., Markesbery, W.R., and Lovell, M.A. (2008). Altered 8-oxoguanine glycosylase in mild cognitive impairment and late-stage Alzheimer’s disease brain. Free Radic. Biol. Med. 45, 813–819. Search in Google Scholar

Singh, A. and Kumar, A. (2008). Protective effect of alprazolam against sleep deprivation-induced behavior alterations and oxidative damage in mice. Neurosci. Res. 60, 372–379. Search in Google Scholar

Smith, J. (2003). Stress and aging: theoretical and empirical challenges for interdisciplinary research. Neurobiol. Aging 24 (Suppl 1), 77–80; discussion 81–82. Search in Google Scholar

Solas, M., Aisa, B., Tordera, R.M., Mugueta, M.C., Ramírez, M.J. (2013). Stress contributes to the development of central insulin resistance during aging: implications for Alzheimer’s disease. Biochim Biophys Acta 1832, 2332–2339. Search in Google Scholar

Sorrells, S.F, Caso, J.R, Munhoz, C.D., and Sapolsky, R.M. (2009). The stressed CNS: when glucocorticoids aggravate inflammation. Neuron 64, 33–39. Search in Google Scholar

Sotiropoulos, I., Catania, C., Riedemann, T., Fry, J.P., Breen, K.C., Michaelidis, T.M., and Almeida, O.F. (2008). Glucocorticoids trigger Alzheimer disease-like pathobiochemistry in rat neuronal cells expressing human tau. J. Neurochem. 107, 385–397. Search in Google Scholar

Sotiropoulos, I., Catania, C., Pinto, L.G., Silva, R., Pollerberg, G.E., Takashima, A., Sousa, N., and Almeida, O.F. (2011). stress acts cumulatively to precipitate Alzheimer’s disease-like tau pathology and cognitive deficits. J. Neurosci. 31, 7840–7847. Search in Google Scholar

Srivareerat, M., Tran, T.T., Alzoubi, K.H., and Alkadhi, K.A. (2009). Chronic psychosocial stress exacerbates impairment of cognition and long-term potentiation in β-amyloid rat model of Alzheimer’s disease. Biol. Psychiatry 65, 918–926. Search in Google Scholar

Starkov, A.A. (2008). The role of mitochondria in reactive oxygen species metabolism and signaling. Ann. NY Acad. Sci. 1147, 37–52. Search in Google Scholar

Stephan, A. and Phillips, A.G. (2005). A case for a non-transgenic animal model of Alzheimer’s disease. Genes Brain Behav. 4, 157–172. Search in Google Scholar

Sultana, R. and Butterfield, D.A. (2009). Oxidatively modified, mitochondria-relevant brain proteins in subjects with Alzheimer disease and mild cognitive impairment. J. Bioenerg. Biomembr. 41, 441–446. Search in Google Scholar

Tanzi, R.E. (2005). The synaptic abeta hypothesis of Alzheimer disease. Nat. Neurosci. 8, 977–979. Search in Google Scholar

Tomás-Camardiel, M., Rite, I., Herrera, A.J., de Pablos, R.M., Cano, J., Machado, A., and Venero, J.L. (2004). Minocycline reduces the lipopolysaccharide-induced inflammatory reaction, peroxynitrite-mediated nitration of proteins, disruption of the blood-brain barrier, and damage in the nigral dopaminergic system. Neurobiol. Dis. 16, 190–201. Search in Google Scholar

Tran, T.T., Srivareerat, M., and Alkadhi, K.A. (2010). Chronic psychosocial stress triggers cognitive impairment in a novel at-risk model of Alzheimer’s disease. Neurobiol. Dis. 37, 756–763. Search in Google Scholar

Tsolaki, M., Pantazi, C., Stiliou, F., Aminta, M., Diudi, P., Karasoulas Kazis, A., and Pollen, D. (2003). Prevalence of dementia in Greek Orthodox Monasteries: the role of diet poor in lipids. Brain Aging 3, 13–17. Search in Google Scholar

Tsolaki, M., Papaliagkas, V., Kounti, F., Messini, C., Boziki, M., Anogianakis, G., and Vlaikidis, N. (2010). Severely stressful events and dementia: a study of an elderly Greek demented population. Psychiatry Res. 176, 51–54. Search in Google Scholar

Vassar, R. (2001). The β-secretase, BACE: a prime drug target for Alzheimer’s disease. J. Mol. Neurosci. 17, 157–170. Search in Google Scholar

Velliquette, R.A., O’Connor, T., and Vassar, R. (2005). Energy inhibition elevates β-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer’s disease pathogenesis, J. Neurosci. 25, 10874–10883. Search in Google Scholar

Velliquette, R.A., O’Connor, T., and Vassar, R. (2006). Energy inhibition elevates β-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer’s disease pathogenesis. J. Neurosci. 26, 2140–2142. Search in Google Scholar

Villarán, R.F., de Pablos, R.M., Argüelles, S., Espinosa-Oliva, A.M., Tomás-Camardiel, M., Herrera, A.J., Cano, J., and Machado, A. (2009). The intranigral injection of tissue plasminogen activator induced blood-brain barrier disruption, inflammatory process and degeneration of the dopaminergic system of the rat. Neurotoxicology 30, 403–413. Search in Google Scholar

Virgin, C.E.Jr., Ha, T.P., Packan, D.R., Tombaugh, G.C., Yang, S.H., Horner, H.C., and Sapolsky, R.M. (1991). Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity. J. Neurochem. 57, 1422–1428. Search in Google Scholar

Wang, J., Dickson, D. W., Trojanowski, J. Q., and Lee V. M. (1999). The levels of soluble versus insoluble brain Aβ distinguish Alzheimer’s disease from normal and pathologic aging. Exp. Neurol. 158, 328–337. Search in Google Scholar

Ward, P.A. and Till, G.O. (1990). Pathophysiologic events related to thermal injury of skin. J. Trauma. 30, 75–79. Search in Google Scholar

Wilson, R.S., Evans, D.A., Bienias, J.L., Mendes de Leon, C.F., Schneider, J.A., and Bennett, D.A. (2003). Proneness to psychological distress is associated with risk of Alzheimer’s disease. Neurology 61, 1468–1469. Search in Google Scholar

Wilson, R.S., Barnes, L.L., Bennett, D.A., Li, Y., Bienias, J.L., Mendes de Leon, C.F., and Evans, D.A. (2005). Proneness to psychological distress and risk of Alzheimer disease in a biracial community. Neurology 64, 380–382. Search in Google Scholar

Wilson, R.S., Arnold, S.E., Schneider, J.A., Kelly, J.F., Tang, Y., and Bennett, D.A. (2006). Chronic psychological distress and risk of Alzheimer’s disease in old age. Neuroepidemiology 27, 143–53. Search in Google Scholar

Yamaguchi, S., Meguro, K., Itoh, M., Hayasaka, C., Shimada, M., Yamazaki, H., and Yamadori, A. (1997). Decreased cortical glucose metabolism correlates with hippocampal atrophy in Alzheimer’s disease as shown by MRI and PET. J. Neurol. Neurosurg. Psychiatry 62, 596–600. Search in Google Scholar

Yankner, B.A. and Lu, T. (2009). Amyloid β-protein toxicity and the pathogenesis of Alzheimer disease. J. Biol. Chem. 284, 4755–4759. Search in Google Scholar

Yankner, B.A., Lu, T., and Loerch, P. (2008). The aging brain. Annu. Rev. Pathol. 3, 41–66. Search in Google Scholar

Yasuno, F., Imamura, T., Hirono, N., Ishii, K., Sasaki, M., Ikejiri, Y., Hashimoto, M., Shimomura, T., Yamashita, H., and Mori, E. (1998). Age at onset and regional cerebral glucose metabolism in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 9, 63–67. Search in Google Scholar

Youdim, M.B., Banerjee, D.K, Kelner, K., Offutt, L., and Pollard, H.B. (1989). Steroid regulation of monoamine oxidase activity in the adrenal medulla. FASEB J. 3, 1753–1759. Search in Google Scholar

Zafir, A. and Banu, N. (2009). Modulation of in vivo oxidative status by exogenous corticosterone and restraint stress in rats. Stress 12, 167–177. Search in Google Scholar

Zamzami, N., Marzo, I., Susin, S.A., Brenner, C., Larochette, N., Marchetti, P., Reed, J., Kofler, R., and Kroemer, G. (1998). The thiol crosslinking agent diamide overcomes the apoptosis-inhibitory effect of Bcl-2 by enforcing mitochondrial permeability transition. Oncogene 26, 1055–1063. Search in Google Scholar

Received: 2014-5-16
Accepted: 2014-7-11
Published Online: 2014-8-29
Published in Print: 2014-12-1

©2014 by De Gruyter