title: 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.affiliation: *Department of Environmental Health Sciences.
authors.forename: Hasina
authors.initials: H
authors.lastname: Akhter
authors.affiliation: *Department of Environmental Health Sciences.
authors.forename: Carol
authors.initials: C
authors.lastname: Ballinger
authors.affiliation: Department of Biostatistics, School of Public Health.
authors.forename: Nianjun
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Cell, Developmental and Integrative Biology, and.
authors.forename: Thomas
authors.initials: T
authors.lastname: van Groen
authors.affiliation: *Department of Environmental Health Sciences.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Postlethwait
authors.affiliation: *Department of Environmental Health Sciences, Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 rliu@uab.edu.
authors.forename: Rui-Ming
authors.initials: RM
authors.lastname: Liu
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000523:psychology*; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000523:psychology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010126:Ozone / Q000633:toxicity*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics; D053763:Presenilins / Q000096:biosynthesis / Q000235:genetics; D012727:Sex Characteristics
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D010446:Peptide Fragments; D053763:Presenilins; C078592:amyloid beta-protein (1-40); D010126:Ozone; D019255:NADPH Oxidases
keywords: Alzheimer’s disease; gender; oxidative stress; ozone