Immunocytochemical evidence that amyloid β (1–42) impairs endogenous antioxidant systems in vivo

doi:10.1016/S0306-4522(02)00993-4

Neuroscience

Volume 119, Issue 2, 27 June 2003, Pages 399-419

https://doi.org/10.1016/S0306-4522(02)00993-4 Get rights and content

Abstract

Amyloid β, the major constituent of the senile plaques in the brains of patients with Alzheimer’s disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. We have previously demonstrated that potent antioxidants idebenone and α-tocopherol prevent learning and memory impairment in rats which received a continuous intracerebroventricular infusion of amyloid β, suggesting a role for oxidative stress in amyloid β-induced learning and memory impairment. To test the hypothesis, in the present study, we investigated alterations in the immunoreactivity of endogenous antioxidant systems such as mitochondrial Mn–superoxide dismutase, glutathione, glutathione peroxidase and glutathione-S-transferase following the continuous intracerebroventricular infusion of amyloid β for 2 weeks. The infusion of amyloid β (1–42) resulted in a significant reduction of the immunoreactivity of these antioxidant substances in such brain areas as the hippocampus, parietal cortex, piriform cortex, substantia nigra and thalamus although the same treatment with amyloid β (40–1) had little effect. The alterations induced by amyloid β (1–42) were not uniform, but rather specific for each immunoreactive substance in a brain region-dependent manner.

These results demonstrate a cytological effect of oxidative stress induced by amyloid β (1–42) infusion. Furthermore, our findings may indicate a heterogeneous susceptibility to the oxidative stress produced by amyloid β.

Section snippets

Experimental procedures

The rats used in the present study were males of the Wistar strain (7 weeks old; Charles River Japan Inc., Yokohama, Japan) weighing 250±20 g at the beginning of experiments. They were housed in groups of two or three in a temperature- and light-controlled room (23 °C; 12-h light/dark cycle starting at 9:00 a.m.) and had free access to food and water. All efforts were made to minimize animal suffering, to reduce the number of animals used, and to utilize alternatives to in vivo techniques, if

Changes in Mn-SOD-like immunoreactivity in the Aβ-treated rats

Since the mitochondria are significant intracellular sources of superoxide radical and hence important targets of oxidative stress, and since the cytosolic Cu,Zn-SOD does not appear to be able to cross the mitochondrial membrane to aid in scavenging superoxide radical in mitochondria, Mn-SOD seems to be responsible for protecting mitochondria from superoxide radical. The existence of Mn-SOD is thus considered to be indirect evidence of the presence of superoxide radical, whether generated

Discussion

In the present study, we demonstrated a significant reduction in the immunoreactivities of Mn-SOD, GSH, GPx, and GST-π in brains of rats which received a continuous infusion of Aβ (1–42), but not Aβ (40–1), into the cerebral ventricle for 2 weeks. Importantly, the alterations induced by Aβ (1–42) were not uniform, but rather specific for each immunoreactive substance in a region-dependent manner. Similarly, a spatiotemporal expression of brain-derived neurotrophic factor mRNA (Tang et al., 2000)

Conclusions

In this study we found that the continuous intracerebroventricular infusion of Aβ (1–42) in rats resulted in a significant decrease of the immunoreactivities of Mn-SOD, GSH, GPx and GST-π in the brain, suggesting that Aβ (1–42) impairs scavenging capacity in a region-dependent manner. These results demonstrate cytological effect of oxidative stress induced by Aβ (1–42) infusion. Furthermore, our findings may indicate a heterogeneous susceptibility to the oxidative stress produced by Aβ.

Acknowledgements

This study was supported in part by Grants-in-Aid for Science Research (No.14370031), a COE Grant and Special Coordination Funds for Promoting Science and Technology, Target-Oriented Brain Science Research Program, from the Ministry of Education, Culture, Sports, Science and Technology of Japan and an SRF Grant for Biomedical Research.

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CellularImmunocytochemical evidence that amyloid β (1–42) impairs endogenous antioxidant systems in vivo

Abstract

Section snippets

Experimental procedures

Changes in Mn-SOD-like immunoreactivity in the Aβ-treated rats

Discussion

Conclusions

Acknowledgements

Prog Neurobiol

Cell

Biochem Biophys Res Commun

Adv Cancer Res

Free Rad Biol Med

Brain Res

J Biol Chem

Eur J Pharmacol

Brain Res

Neurosci Lett

Brain Res

Trends Neurosci

Brain Res

Brain Res

Neurobiol Aging

Exp Neurol

Free Radic Biol Med

Neurobiol Aging

Brain Res

J Biol Chem

J Biol Chem

Exp Neurol

Neurosci Lett

Jpn J Pharmacol

Trends Cell Biol

Neuron

Biochem Biophys Res Commun

Mol Brain Res

Neuroscience

Pharmacol Ther

Neurosci Lett

Neuron

The expression of key oxidative stress-handling genes in different brain regions in Alzheimer’s disease

J Mol Neurosci

Vitamin E protects nerve cells from amyloid β protein toxicity

Biochem Biophys Res Commun

4-Hydroxynonenal, a product of lipid peroxidation, damages cholinergic neurons and impairs visuospatial memory in rats

J Neuropathol Exp Neurol

Differential localization of glutathione-S-transferase Yp and Yb subunits in oligodendrocytes and astrocytes of rat brain

J Neurochem

Free radical damage to protein and DNAmechanism involved and relevant observations on brain undergoing oxidative stress

Ann Neurol

Cellular
Immunocytochemical evidence that amyloid β (1–42) impairs endogenous antioxidant systems in vivo

Differential localization of glutathione-S-transferase Y_p and Y_b subunits in oligodendrocytes and astrocytes of rat brain