Abstract
Oxidative stress in the olfactory system is a major factor associated with age‐related olfactory impairment, although the mechanisms by which this occurs are not completely understood. The Harlequin mutant mouse (Hq/Y), which carries an X‐linked recessive mutation in the Aifm1 gene, is a model of progressive oxidative stress–induced neurodegeneration in the cerebellum and retina. To determine whether the Hq/Y mutant mouse is a suitable model of oxidative stress–associated olfactory aging, we investigated cellular and molecular changes in the olfactory epithelium (OE) and olfactory bulb (OB) of 6‐month‐old male Hq/Y mice compared to those in sex‐matched littermate controls (+/Y) and in age‐ and sex‐matched C57BL/6 mice. Immunoreactivity for apoptosis‐inducing factor, the protein product of Aifm1, was localized in mature olfactory sensory neurons (mOSNs) in +/Y mice but was rarely detected in Hq/Y mice. Hq/Y mice also exhibited increased lipofuscin autofluorescence and increased immunoreactivity for an oxidative DNA/RNA damage marker in mOSNs and in mitral/tufted cells in the OB and an increased number of cleaved caspase‐3 immunoreactive apoptotic cells in the OE. Microarray analysis demonstrated that Aifm1 expression was down‐regulated by 80% in the OE of Hq/Y mice compared to that in +/Y mice. Most significantly, regulated genes were classified into functional categories of cell signaling/apoptosis/cell cycle, oxidative stress/aging, and cytoskeleton/extracellular matrix/transport‐associated. Analysis with EASE software indicated that the functional categories significantly overrepresented in Hq/Y mice included up‐regulated mitochondrial genes and down‐regulated cytoskeletal organization‐ and neurogenesis‐related genes. Our results strongly support the Hq/Y mutant mouse being a novel model for mechanistic studies of oxidative stress–associated olfactory aging. © 2007 Wiley‐Liss, Inc.