Figure 4.

Design of studies to elucidate the effects of diabetes and Ex-4 on glucose metabolism and AD-like neuropathology in 3xTg-AD mice. A) Scheme of animal study: 3xTgAD mice were assigned to four groups: (i) controls received vehicle (sodium citrate buffer) for 5 consecutive days; (ii) STZ (2-deoxy-2-(3-methyl-3-nitrosoureido)-D-glucopyranose: a well-characterized pancreatic β-cell toxin) for 5 consecutive days (50 mg/kg, i.p.); (iii) Ex-4 alone received vehicle for 5 consecutive days; (iv) STZ+Ex-4 received STZ (50 mg/kg i.p.) for 5 consecutive days. Body weight and blood glucose levels were monitored once every other day during the STZ treatment week and, thereafter, once weekly for the duration of the study (16 weeks). In Ex-4 treated groups (Ex-4 alone and STZ+Ex-4), Ex-4 was delivered by subcutaneously implanted pump initiated 3 days after the final STZ dose. Vehicle (saline) pumps were implanted into control and STZ alone groups, and the pumps were replaced every 4 weeks. Each animal received an intraperitoneal glucose tolerance test (IPGTT) on weeks 7 and 15, and was euthanized at 16 weeks. B) Time-dependent blood glucose levels (mg/dL ± SEM) in control, STZ (diabetic), Ex-4 and STZ+Ex-4 3xTg-AD mice. Both groups administered STZ (STZ and STZ+Ex-4) were hyperglycemic, compared to controls (p<0.01, Tukey’s multiple comparison test); however, Ex-4 treatment (STZ+Ex-4) ameliorated the rise in blood glucose levels (p<0.001, vs. STZ alone, Tukey’s test). Blood glucose levels in control and Ex-4 alone mice were no different throughout the study (p>0.05, Tukey’s test).