Establishing a Type 2 Diabetes phenotype in APPxhQC transgenic mice expressing N‐terminally modified pGlu Aβ peptides.

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of amyloid beta (Aβ) plaques in the brain. Aβ peptides are commonly subjected to post‐translational modifications like truncation known to play pivotal role in Aβ plaque aggregation. N‐terminally truncated Aβ peptides containing pyroglutamatic acid (pGlu) catalyzed by glutaminyl cyclase (QC) e.g., pGlu3‐Aβ (3‐40/42) are the major Aβ peptide fragments within the core of the neuritic plaques and correlate with disease severity and progression. Type 2 diabetes (T2D) is one of the major risk factors associated with AD and compelling evidence supports the notion that insulin resistance, a key feature of T2D, is involved in AD‐type neurodegeneration. Hence, in this study, we aim to establish a T2D phenotype in APPxhQC transgenic using low‐dose Streptozocin injection in combination with high fat diet (HFD).MethodsAPPxhQC mice, crossbreds of APPSL and hQC mice, were used. APPSL mice express human APP751 with the Swedish and the London mutation on a C57Bl/6RccHsd background. hQC mice on B6CBAF1/J background express human glutaminyl cyclase (QC) enzyme. The cross‐breeding results in an increased generation of N‐terminal modified pGlu Aβ peptides. To establish a T2D phenotype, 8‐9 months old APPxhQC transgenic mice were allocated to 4 treatment groups receiving: standard chow diet, HFD, standard chow diet in combination with streptozocin injections and HFD in combination with streptozocin injections. The intraperitoneal glucose tolerance test (ipGTT) and intraperitoneal insulin tolerance test (ipITT) were performed at 6 and 7 weeks after the initiation of the diet, as a relevant parameter of T2D progression.ResultsStreptozocin‐injected mice maintained on HFD had the least tolerance to injected glucose as shown by ipGTT. Impaired glucose clearance was observed at 15, 30, 60 and 120 mins after intraperitoneal glucose injection (2g/kg). Also, impaired glucose clearance at 15 mins after intraperitoneal insulin injection (0.75U/kg) was observed in the same group.ConclusionCombination of high‐fat diet and streptozocin injections leads to the development of robust T2D symptoms in APPxhQC transgenic mice. Current experiments are focusing on combinational effects of T2D and post‐translationally modified amyloid peptides in AD progression and pathophysiology.