Letrozole Potentiates Mitochondrial and Dendritic Spine Impairments Induced by<i>β</i>Amyloid

Abstract

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 (Aβ 1-42) has not been established. The objective of this study was to determine if letrozole aggravates synaptic deficits concurrent with Aβ 1-42 insult. We examined the effects of letrozole and oligomeric Aβ 1-42 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 Aβ 1-42 oligomers. Oligomeric Aβ 1-42 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 Aβ 1-42 treatment. Our novel findings suggest that letrozole may increase neuronal susceptibility to pathological insults, such as oligomeric Aβ 1-42 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.