Fig. 3: CP2 treatment increases glucose uptake and utilization in symptomatic APP/PS1 mice.

a Glucose uptake was increased in the brain of CP2-treated APP/PSI mice measured using FDG-PET after 1 - 2.6 months of treatment in two independent cohorts of mice. Representative images are from one of the cohorts. b Quantification of glucose uptake by FDG-PET imaging from a. NTG, n = 7 mice per group; NTG + CP2, n = 4 mice per group; APP/PS1, n = 5 mice per group; APP/PS1 + CP2, n = 10 mice per group. c Changes in respiratory exchange rate (RER) recorded in all treatment groups over 44 h during ad lib fed and fasting states in mice treated for 9 months. d Glucose oxidation was increased in CP2-treated APP/PS1 mice fed ad lib based on CLAMS data from c. Gray bars indicate fat consumption; orange bars indicate carbohydrate and protein oxidation. e Metabolic flexibility is increased in CP2-treated APP/PS1 mice based on their ability to switch from carbohydrates to fat between feeding and fasting states. c–e NTG, n = 16 mice per group; NTG + CP2, n = 20 mice per group; APP/PS1, n = 15 mice per group; APP/PS1 + CP2, n = 19 mice per group. f–h CP2 treatment reduces fasting insulin levels in plasma of APP/PS1 mice (f); increases glucose tolerance in NTG mice measured by intraperitoneal glucose tolerance test (IPGTT) (g); and displays tendency to improve intraperitoneal insulin sensitivity test (IPIST) in NTG and APP/PS1 mice (h) after 9–10 months of treatment. n = 5 mice per group. The outliers in (h) included 1 NTG+CP2 and 2 APP/PS1+CP2 mice that were excluded from the graph. i Western blot analysis conducted in the brain tissue of APP/PS1 mice treated with CP2 for 13 months indicates increased IGF-1signaling, expression of Glut 3 and 4 transporters and changes in pyruvate dehydrogenase (PDH) activation associated with glucose utilization in the TCA cycle. j Representative ³¹P NMR spectra with peaks corresponding to energy metabolites, including inorganic phosphate (Pi), phosphocreatine (PCr), and three phosphate group peaks for ATP generated in living NTG and APP/PS1 mice after 9 months of vehicle or CP2 treatment. k Phosphocreatine/ATP ratio calculated based on the ³¹P NMR in vivo spectra from j. NTG, n = 4 mice per group; NTG + CP2, n = 3 mice per group; APP/PS1, n = 6 mice per group; APP/PS1 + CP2, n = 6 mice per group. Data are presented as mean ± S.E.M. Data were analyzed by two-way ANOVA with Fisher’s LSD post-hoc test. *P < 0.05, **P < 0.01. In all graphs: APP/PS1, orange line; NTG, black line; NTG + CP2, blue line; APP/PS1 + CP2, red line.