Figure 1

db/AD characteristics. The diabetic Lepr ^db/db mouse was crossed to the APP/PS1 knock-in model of AD to create the db/AD line. (a) Mice homozygous for the db gene were obese (female, 9 months old; left: Lepr ^db/db mouse; right: Lepr ^db/+ mouse). (b) Lepr ^db/db mice showed an impaired response to glucose (F[2,30] = 38.2, p ≤ 0.0001 for the db genotype overall, n = 13 Lepr ^+/+, n = 5 Lepr ^db/+, n = 18 Lepr ^db/db; ** = p ≤ 0.01, * = p ≤ 0.05, Tukey’s LSD). The AD genotype did not affect the GTT (not shown). (c - d) Lepr ^db/db mice showed substantial weight gain from an early age. Weight was relatively stable after ~7 months, and there was no effect of the AD genotype (* = p ≤ 0.01, t-test; Holm-Bonferroni [27] correction; n = ~14 mice / genotype). Female (e) and male (f) Lepr ^db/db x APP ^ΔNL/ΔNL /PS1 ^p264L/P264L mice had reduced survivability compared with other genotypes, though the males had a particularly high attrition rate. (N = 367 F/359 M: Lepr ^db/db x APP ^ΔNL/ΔNL /PS1 ^p264L/P264L, n = 56 F/53 M; Lepr ^db/db x APP ^+/+ / PS1 ^+/+ , n = 73 F/60 M; Lepr ^+/+ x APP ^ΔNL/ΔNL /PS1 ^p264L/P264L, n = 54 F/44 M; Lepr ^+/+ x APP ^+/+ / PS1 ^+/+, n = 56 F/61 M; Lepr ^db/+ × APP ^ΔNL/ΔNL /PS1 ^P264L/P264L, n = 69 F/61 M; Lepr ^db/+ × APP ^+/+ / PS1 ^+/+, n = 59 F/80 M) In subsequent experiments, we focused on the four main genotypes. For simplicity we have named them WT, db, AD, and db/AD. (g) Lepr ^db/db (db and db/AD) mice were insulin resistant (F[15,177] = 4.64, p ≤ 0.0001 for the db genotype overall; WT, n = 14; db, n = 13; AD, n = 20; db/AD, n = 18; ~6 months of age; * = p ≤ 0.05, ** = p ≤ 0.01; Dunnett’s test, relative to Lepr ^+/+ (WT and AD)). (h) Blood pressure was not different, although there was a modest tendency (F[2,15] = 3.24, p ≤ 0.1) for it to be slightly lower overall in Lepr ^db/db mice regardless of the AD genotype, at least at this age (n = 5–7 mice / genotype, ~7-8 months of age).