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Letrozole Potentiates Mitochondrial and Dendritic Spine Impairments Induced by β Amyloid

DOI: 10.1155/2013/538979

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Reduced estrogens, either through aging or postsurgery breast cancer treatment with the oral nonsteroidal aromatase inhibitor letrozole, are linked with declined cognitive abilities. However, a direct link between letrozole and neuronal deficits induced by pathogenic insults associated with aging such as beta amyloid ( ) has not been established. The objective of this study was to determine if letrozole aggravates synaptic deficits concurrent with insult. We examined the effects of letrozole and oligomeric treatment in dissociated and organotypic hippocampal slice cultures. Changes in glial cell morphology, neuronal mitochondria, and synaptic structures upon letrozole treatment were monitored by confocal microscopy, as they were shown to be affected by oligomers. Oligomeric or letrozole alone caused decreases in mitochondrial volume, dendritic spine density, synaptophysin (synaptic marker), and the postsynaptic protein, synaptopodin. Here, we demonstrated that mitochondrial and synaptic structural deficits were exacerbated when letrozole therapy was combined with treatment. Our novel findings suggest that letrozole may increase neuronal susceptibility to pathological insults, such as oligomeric in Alzheimer’s disease (AD). These changes in dendritic spine number, synaptic protein expression, and mitochondrial morphology may, in part, explain the increased prevalence of cognitive decline associated with aromatase inhibitor use. 1. Introduction Currently, aromatase inhibitors, leading to reduction of estradiol synthesis from testosterone, have been favoured in the treatment of breast cancer of postmenopausal women [1]. Letrozole is one such oral nonsteroidal aromatase inhibitor which prevents the aromatase from producing estrogens by competitive, reversible binding to the heme of its cytochrome P450 unit [2, 3]. Patients receiving letrozole have shown deficits in learning and memory [4]. However, it is still unclear if these functional impairments occur because of neurosteroid deficits and if they become exacerbated in the presence of an additional insult associated with aging, such as an excess of soluble, conformationally altered . Such forms of can interact with synapses and cause pronounced degenerative changes, an observation made in brain tissue from postmortem Alzheimer’s disease (AD) patients and animal models [5]. It has been well documented in AD that there are changes in neuronal and glial morphologies such as dendritic spine atrophy and increased glial growth [5, 6]. In contrast to these negative effects caused by , it is well established that

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