Rosiglitazone reversal of Tg2576 cognitive deficits is independent of peripheral gluco-regulatory status

Abstract

Converging lines of evidence associate gluco-regulatory abnormalities and peroxisome-proliferator-activated receptor (PPAR) gamma function with increased risk for Alzheimer's disease (AD). In this study, we used the Tg2576 AD mouse model to test the hypothesis that cognitive improvement following 1 month of PPAR gamma agonism with rosiglitazone (RTZ) correlates with peripheral gluco-regulatory status. We assessed cognition and peripheral gluco-regulatory status of Tg2576 mice following 1 month treatment with RTZ initiated prior to, coincident with, or after, the onset of peripheral gluco-regulatory abnormalities (4, 8, and 12 months of age, respectively). Whereas 5 months old (MO) and 13 MO Tg2576 did not gain cognitive improvement after 1 month treatment with RTZ, 9 MO Tg2576 mice exhibited reversal of associative learning and memory deficits. Peripheral gluco-regulatory abnormalities were improved in 9 and 13 MO Tg2576 with RTZ treatment; RTZ treatment had no effect on the normal glucose status of 5 MO Tg2576 mice. These findings suggest that RTZ-mediated cognitive improvement does not correlate with peripheral gluco-regulatory abnormalities per se, but reflects the age-dependent mechanistic differences that underlie cognitive decline in this mouse model.

Figure 1. Older, 9 and 12 MO, Tg2576 exhibit hyperinsulinemia

Tail blood was collected under fasting conditions. Samples were processed to obtain the serum, and serum insulin levels determined with LINCOplex kit (Millipore). a, 5 MO Tg2576 insulin levels were not significantly different from WT littermates. (one-way ANOVA F(3,49)=1.33; p=0.28). b, 9 MO Tg2576 demonstrated significantly higher insulin levels compared to WT littermates (one-way ANOVA F(3,41)=4.11; p=0.01). Treatment with RTZ significantly lowered serum insulin in Tg2576 mice (p>0.05) * indicates significance compared to WT on control diet; + indicates significance compared to Tg2576 on control diet). c, Similar to 9 MO Tg2576, 13 MO Tg2576 had significantly higher serum insulin levels than WT littermates (one-way ANOVA F(3,81)=5.47; p=0.002). Hyperinsulinemia in 13 MO Tg2576 was reversed with RTZ treatment. * indicates significance compared to WT on control diet; + indicates significance compared to Tg2576 on control diet.

Figure 2. Tg2576 exhibit age-selective dysregulation of glucose

a, GTT performed on 5 MO Tg2576 (□) demonstrated normal glucose clearance, when compared to WT littermates (○) (one-way repeated measures ANOVA F(3,15) = 3.17; p=0.06). RTZ had no effect on the glucose clearance in neither, Tg2576 (∇) nor WT (∆), genotype at 5 MO. b, 9 MO Tg2576 exhibit impaired glucose clearance compared to WT (one-way repeated measures ANOVA F(3,15)=7.15; p=0.003). One-way ANOVA revealed that Tg2576 on control diet exhibited significantly different glucose levels at the 15, 30 and, 60 min time points (15 min: F(3,55) = 6.51, p=0.001; 30 min: F(3,55)=4.88, p=0.005; and 60 min: F(3,55)=2.72, p=0.05). * indicates statistical significance [p<0.05] compared to WT. Treatment with RTZ normalized glucose clearance in 9 MO Tg2576 (one-way repeated measures ANOVA F(3,15)=7.15; p>0.05). c, 13 MO Tg2576 performance in GTT is altered (one-way repeated measures ANOVA F(3,15)= 9.88; p=0.001). One-way ANOVA revealed that Tg2576 on control diet have lower glucose levels at 90, and 120 min than WT (90 min: F(3,46)=3.25, p=0.03; 120 min: F(3,46)=3.25, p=0.03) * indicates significance compared to WT. Thirteen MO Tg2576 mice treated with RTZ cleared glucose similarly to WT treated and untreated (one-way repeated measures ANOVA F(3,15)=9.876; p>0.05.

Figure 3. RTZ reverses learning and memory deficits in 9 MO Tg2576

a, RTZ treatment did not rescue the contextual fear conditioning deficit in 5 MO Tg2576 (one-way ANOVA F(3,16)=26.07, p<0.0001). * indicates statistical significance compared to WT on control diet; ≠ indicates significance compared to WT treated with RTZ ; + indicates significance compared to Tg2576 on control diet. b, Treatment with RTZ reversed the fear conditioning deficit in 9 MO Tg2576. (one-way ANOVAF(3,16)=11.95; p<0.0001; * indicates statistical significance compared to WT on control diet; ≠ indicates significance compared to WT treated with RTZ ; + indicates significance compared to Tg2576 on control diet. c, RTZ treatment did not improve cognition in 13 MO Tg2576 (one-way ANOVA F(3,16)=14.16; p<0.0001; * indicates significance compared to WT on control diet; ≠ indicates significance compared to WT treated with RTZ.

Figure 4. Schematic illustration of cognitive performance in Tg2576 and wild type littermate mice as a function of age

Based on our and others’ work we can illustrate the cognitive decline exhibited by Tg2576 mice (gray solid line), compared to wild type mice (black solid line), over the lifespan of these animals [,–20]. One month RTZ treatment initiated around the onset of gluco-regulatory abnormalities (8 MO) reverses cognitive deficits in Tg2576 mice (gray dotted line). RTZ treatment that is initiated prior to manifestation of gluco-regulatory abnormalities (4 MO) or long after the onset of gluco-regulatory abnormalities (12 MO) are unsuccessful at rescuing cognitive function. These findings suggest a limited therapeutic window for effective RTZ treatment on cognition in Tg2576 AD mice.