Investigating the role of estrogen deprivation and diet-induced insulin resistance on markers of amyloid-β production and degradation in the brain

Abstract

Estrogen loss, which women experience during menopause, has recently been associated with increased amyloid-β (Aβ) peptides, a main feature of Alzheimer’s Disease (AD). Furthermore, diet-induced insulin resistance has also been shown to increase Aβ; however, whether this process is exacerbated with the loss of estrogen remains unknown. We aimed to investigate the effects of estrogen loss on amyloid production and degradation pathways, as well as markers of insulin signaling, glucose uptake and synaptic function, in an insulin resistant mouse model. To do this, female C57BL/6J mice received either bilateral ovariectomy, to simulate estrogen loss, (OVX; n=20) or remained intact (n=20) at 24 weeks of age. Mice were then placed on either a low or high fat diet (LFD; n=10 for OVX and intact, HFD; n=10 for OVX and intact) for 10 weeks to induce insulin intolerance. Prefrontal cortex and hippocampus tissues were then isolated and markers of amyloidogenesis, Aβ degradation, insulin signaling, glucose uptake, and synaptic function were examined. Independently, OVX led to increases in the amyloidogenic marker, sAPPβ. Furthermore, HFD combined with OVX, led to lower IDE protein content and activity in the prefrontal cortex, indicative of decreased Aβ degradation. Lastly, HFD with OVX led to exacerbated decreases in pGSK-3β /GSK, GLUT1, and Homer-1 (a postsynaptic marker) in the hippocampus, and GLUT3 in the prefrontal cortex. Data from this study provide evidence of a synergistic effect of systemic insulin resistance and estrogen loss in decreasing brain markers of Aβ degradation, insulin signaling, glucose uptake, and synaptic function. Furthermore, findings indicate how the loss of estrogen can promote the formation of amyloidogenic APP cleavage products, independent of diet-induced insulin resistance. These results ultimately contribute to our understanding of both estrogen-deprivation and insulin resistance on female brain health in relation to AD progression.