Cyclic Ozone Exposure Induces Gender-Dependent Neuropathology and Memory Decline in an Animal Model of Alzheimer's Disease.

Abstract

Alzheimer's disease (AD) is a major cause of dementia in the elderly. Although early-onset (familial) AD is attributed to gene mutations, the cause for late-onset (sporadic) AD, which accounts for 95% of AD cases, is unknown. In this study, we show that exposure of 6-week-old amyloid beta precursor protein (APP)/presenilin (PS1) overexpressing mice, a well-established animal model of AD, and nontransgenic littermates to a cyclic O3 exposure protocol, which mimics environmental exposure episodes, accelerated learning/memory function loss in male APP/PS1 mice but not in female APP/PS1 mice or nontransgenic littermates. Female APP/PS1 mice had higher brain levels of amyloid beta peptide (Aβ42) and Aβ40, compared with male APP/PS1 mice; O3 exposure, however, had no significant effect on brain Aβ load in either male or female mice. Our results further show that male APP/PS1 mice had lower levels of antioxidants (glutathione and ascorbate) and experienced augmented induction of NADPH oxidases, lipid peroxidation, and neuronal apoptosis upon O3 exposure, compared with female APP/PS1 mice. No significant effect of O3 on any of these parameters was detected in nontransgenic littermates. In vitro studies further show that 4-hydroxynonenal, a lipid peroxidation product which was increased in the plasma and cortex/hippocampus of O3-exposed male APP/PS1 mice, induced neuroblastoma cell apoptosis. Together, the results suggest that O3 exposure per se may not cause AD but can synergize with genetic risk factors to accelerate the pathophysiology of AD in genetically predisposed populations. The results also suggest that males may be more sensitive to O3-induced neuropathophysiology than females due to lower levels of antioxidants.

• Authors: Hasina Akhter, Carol Ballinger, Nianjun Liu, Thomas van Groen, Edward M Postlethwait, Rui-Ming Liu
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 147 Issue 1 Pg. 222-34 (Sep 2015) ISSN: 1096-0929 [Electronic] United States
• PMID: 26116027 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Amyloid beta-Peptides
• Antioxidants
• Peptide Fragments
• Presenilins
• amyloid beta-protein (1-40)
• Ozone
• NADPH Oxidases

Topics

• Alzheimer Disease (chemically induced, psychology)
• Amyloid beta-Peptides (biosynthesis, genetics)
• Animals
• Antioxidants (metabolism)
• Apoptosis (drug effects)
• Brain Chemistry (drug effects)
• Female
• Lipid Peroxidation (drug effects)
• Male
• Memory Disorders (chemically induced, psychology)
• Mice
• NADPH Oxidases (metabolism)
• Nervous System Diseases (chemically induced, psychology)
• Neurons (drug effects, pathology)
• Ozone (toxicity)
• Peptide Fragments (biosynthesis, genetics)
• Presenilins (biosynthesis, genetics)
• Sex Characteristics