Abstract TP18: Iron Overload Induces Cognitive Deficits And Autophagy Impairment In The Brains Of Aged Mice In A Sex-Dependent Manner

Iron deposits have been observed in postmortem brain samples from Alzheimer’s disease patients. Different iron overload models have been used to study neurodegeneration in young mice. However, the effects of excess iron with aging, which is a critical factor for Alzheimer’s disease and iron deposition in the brain, remain unexplored. In addition, iron metabolism is regulated by autophagy, a cellular process that degrades intracellular components. Brain autophagy is downregulated with aging and in females, and autophagy impairment occurs in many neurodegenerative disorders. Thus, we hypothesized that sex differences exist in autophagy in the brains of aged mice treated with iron overload. We treated aged (18-20 months) WT mice of both sexes with iron overload (5% ferric citrate, FC, 3 days/week/6 weeks), or a vehicle, by oral gavage. We found that aged females showed impairment in conditioning memory (Fear conditioning), but not aged males. Aged females treated with FC also showed significant increase of iron deposition in their brains, compared with control females. However, we did not find significant differences between control and treated male mice. Furthermore, the brain lysates of aged females treated with iron overload showed increased levels of the early autophagy marker BECLIN1 (in both sexes), and enhanced levels of the autophagy cargo p62 (in both sexes) and the lysosomal marker LAMP1 (only in females), compared with control mice. This suggests that iron overload induces the initial stage of autophagy in both sexes, but impairs late autophagy, mainly in female mice, compared with control mice. Furthermore, in primary culture of cerebral endothelial cells (CEC) isolated from aged mice, we found that CEC treated with ferric citrate exhibit enhanced DNA damage and reduced cell proliferation in a dose-dependent manner. Importantly, CEC derived from female mice showed reduced autophagy flux, compared with male CEC. This suggests that iron overload may be more detrimental in the cerebrovasculature of aged female mice than in males, and this could explain iron overload-induced memory deficiency in aged female mice, but not in males.