Abstract
Our previous studies reveal that long-term exposure of ovariectomized rodents to d-galactose results in pathophysiologic alterations associated with Alzheimer’s disease. The current study was to address whether mitochondrial dysfunction was involved in the pathogenesis of this model. Ovariectomized mice were administered intraperitoneally with d-galctose (100 mg/kg body weight) once a day for 8 weeks. Brain tissues from model mice showed decreases in reduced glutathione level, total antioxidative capabilities, total superoxide dismutase activity and glutathione peroxidase activity but an increase in malondialdehyde level, compared with those from sham-operated plus saline-injected mice. Activities of brain mitochondrial respiratory chain (complex I, II, III and IV) were reduced in model group. In contrast, ATP synthase (F1F0-ATPase) activity was not significantly different between the two groups. Moreover, electron microscopy identified ultrastructural impairments of hippocampal mitochondria in model mice. These results demonstrated that brain mitochondrial degeneration caused by oxidative stress participated in the etiology of ovarian hormone deprivation and d-galactose-induced neurodegeneration.
Similar content being viewed by others
References
Markesbery WR (1999) The role of oxidative stress in Alzheimer disease. Arch Neurol 56:1449–1452
Perry G, Nunomura A, Hirai K et al (2000) Oxidative damage in Alzheimer’s disease: the metabolic dimension. Int J Dev Neurosci 18:417–421
Chong ZZ, Li F, Maiese K (2005) Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol 75:207–246
Amantea D, Russo R, Bagetta G et al (2005) From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens. Pharmacol Res 52:119–132
Simpkins JW, Dykens JA (2008) Mitochondrial mechanisms of estrogen neuroprotection. Brain Res Rev 57:421–430
Tang MX, Jacobs D, Stern Y et al (1996) Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 348:429–432
Henderson VW (2006) Estrogen-containing hormone therapy and Alzheimer’s disease risk: understanding discrepant inferences from observational and experimental research. Neuroscience 138:1031–1039
Zhang XL, Jiang B, Li ZB et al (2007) Catalpol ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by d-galactose. Pharmacol Biochem Behav 88:64–72
Lei M, Hua X, Xiao M et al (2008) Impairments of astrocytes are involved in the d-galactose-induced brain aging. Biochem Biophys Res Commun 369:1082–1087
Song X, Bao M, Li D et al (1999) Advanced glycation in d-galactose induced mouse aging model. Mech Aging Dev 108:239–251
Ho SC, Liu JH, Wu RY (2003) Establishment of the mimetic aging effect in mice caused by d-galactose. Biogerontology 4:15–18
Wei H, Li L, Song Q et al (2005) Behavioural study of the d-galactose induced aging model in C57BL/6J mice. Behav Brain Res 157:245–251
Chen CF, Lang SY, Zuo PP et al (2006) Effects of d-galactose on the expression of hippocampal peripheral-type benzodiazepine receptor and spatial memory performances in rats. Psychoneuroendocrinology 31:805–811
Cui X, Zuo P, Zhang Q et al (2006) Chronic systemic d-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid. J Neurosci Res 84:647–654
Wu DM, Lu J, Zheng YL et al (2008) Purple sweet potato color repairs d-galactose-induced spatial learning and memory impairment by regulating the expression of synaptic proteins. Neurobiol Learn Mem 90:19–27
Lei M, Su Y, Hua X et al (2008) Chronic systemic injection of d-galactose impairs the septohippocampal cholinergic system in rats. Neuroreport 19:1611–1615
Hsieh HM, Wu WM, Hu ML (2009) Soy isoflavones attenuate oxidative stress and improve parameters related to aging and Alzheimer’s disease in C57BL/6J mice treated with d-galactose. Food Chem Toxicol 47:625–632
Luo Y, Niu F, Sun Z et al (2009) Altered expression of Abeta metabolism-associated molecules from d-galactose/AlCl(3) induced mouse brain. Mech Ageing Dev 130:248–252
Hua X, Lei M, Zhang Y et al (2007) Long-term d-galactose injection combined with ovariectomy serves as a new rodent model for Alzheimer’s disease. Life Sci 80:1897–1905
Hua X, Lei M, Ding J et al (2008) Pathological and biochemical alterations of astrocytes in ovariectomized rats injected with d-galactose: a potential contribution to Alzheimer’s disease processes. Exp Neurol 210:709–718
Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58:495–505
Leuner K, Hauptmann S, Abdel-Kader R et al (2007) Mitochondrial dysfunction: the first domino in brain aging and Alzheimer’s disease? Antioxid Redox Signal 9:1659–1675
Mancuso M, Coppede F, Murri L et al (2007) Mitochondrial cascade hypothesis of Alzheimer’s disease: myth or reality? Antioxid Redox Signal 9:1631–1646
Bosetti F, Brizzi F, Barogi S et al (2002) Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease. Neurobiol Aging 23:371–376.25
Mitchell P (1980) Proton motive cytochrome system of mitochondria. Ann N Y Acad Sci 341:564–584
Zhu XW, Raina AK, Perry G et al (2004) Alzheimer disease: the two-hit hypothesis. Lancet Neurol 3:219–226
Tayebati SK (2006) Animal models of cognitive dysfunction. Mech Ageing Dev 127:100–108
Pratico D, Uryu K, Leight S et al (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 21:4183–4187
Schuessel K, Schafer S, Bayer TA et al (2005) Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice. Neurobiol Dis 18:89–99
Gu F, Zhu M, Shi J et al (2008) Enhanced oxidative stress is an early event during development of Alzheimer-like pathologies in presenilin conditional knock-out mice. Neurosci Lett 440:44–48
Reichmann H, Flörke S, Hebenstreit G et al (1993) Analyses of energy metabolism and mitochondrial genome in post-mortem brain from patients with Alzheimer’s disease. J Neurol 240:377–380
Mutisya EM, Bowling AC, Beal MF (1994) Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 63:2179–2184
Dringen R, Hirrlinger J (2003) Glutathione pathways in the brain. Biol Chem 384:505–516
Seifert G, Schilling K, Steinhauser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7:194–206
Liu H, Wang H, Shenvi S et al (2004) Glutathione metabolism during aging and in Alzheimer disease. Ann N Y Acad Sci 1019:346–349
Acknowledgments
This work was supported by the grants from National Key Basic Research Program of China (2009CB521906), Natural Science Foundation of Jiangsu Province (BK2006576) and Jiangsu Qing Lan Project.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
11064_2009_68_MOESM1_ESM.tif
Morris water-maze testing. (A) Mean latency in the hidden platform test. (B) Comparison of time spent in the target quadrant with other quadrants on day 5. Data are expressed as means ± SEM from 16 mice per group. Comparisons between the two groups were made by using Student’s t-test. Multiple comparisons were performed using repeated measures analysis of variance followed by Bonferroni correction. *P < 0.05, **P < 0.01, OVX plus d-gal-injected group versus sham-operated plus saline-injected group (TIFF 1715 kb)
Rights and permissions
About this article
Cite this article
Su, Y., Sun, H., Fang, J. et al. Brain Mitochondrial Dysfunction in Ovariectomized Mice Injected with d-Galactose. Neurochem Res 35, 399–404 (2010). https://doi.org/10.1007/s11064-009-0068-8
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-009-0068-8