Examining the effects of ovarian hormone loss and diet-induced obesity on Alzheimer's disease markers of amyloid-β production and degradation.

After menopause, women experience declines in ovarian sex hormones, an event that has recently been associated with increased amyloid-β peptides, a main feature of Alzheimer's disease. Diet-induced insulin resistance also increases amyloid-β peptides; however, whether this process is exacerbated with ovarian sex hormone loss remains unknown. Female C57BL6/J mice received either bilateral ovariectomy (OVX; n = 20) or remained intact (n = 20) at 24 wk of age and were 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 wk. Independently, OVX led to increases in the amyloidogenic marker, soluble amyloid precursor protein β (sAPPβ). The HFD in combination with OVX led to lower insulin degrading enzyme (IDE) protein content and activity in the prefrontal cortex, indicative of decreased amyloid-β degradation; however, no differences in amyloid-β content were observed. Data from this study provide novel evidence of independent effects of peripheral insulin resistance and ovarian sex hormone loss in decreasing brain markers of amyloid-β degradation. Furthermore, findings indicate how the loss of ovarian sex hormones can promote the formation of amyloidogenic APP cleavage products, independent of diet-induced insulin resistance.NEW & NOTEWORTHY This study provides novel insight into the effect of peripheral insulin resistance and ovarian hormone loss in decreasing brain markers of amyloid-β degradation. Results demonstrate that ovarian hormone loss through ovariectomy increased the amyloidogenic marker, sAPPβ, while the high-fat diet in combination with ovariectomy led to lower IDE protein content and activity in the prefrontal cortex, indicative of decreased amyloid-β degradation. These original results provide important information for future targets in early AD pathogenesis.