AbstractBackgroundAccumulation of amyloid beta (Aβ) and tau proteins have for decades been thought to be central in the pathogenesis of Alzheimer’s disease (AD). More recently, a plethora of evidence emerged that links metabolic dysfunctions such as obesity, type 2 diabetes (T2D), and dyslipidemia with the pathophysiology of AD. In this study, we investigated the effects of streptozocin and high fat diet (HFD) induced T2D on lipid and amyloid beta metabolism in APPxhQC transgenic mice and their wild‐type littermates.MethodAPPxhQC mice were generated by crossbreeding APPSL with hQC mice. As controls wild‐type littermates were used. APPSL mice express human APP751 with the Swedish and the London mutation on a C57Bl/6RccHsd background. hQC mice express human glutaminyl cyclase (QC) enzyme on B6CBAF1/J background. Plasma lipids (triglycerides and cholesterol) and liver function enzymes (aspartate aminotransferase and alanine transaminase, ALT and ALT, respectively) were determined by ELISA. Brain concentrations of soluble and insoluble Aβ 1‐38, 1‐40 and 1‐42 peptides were determined using an immunosorbent assay (Mesoscale discovery immunosorbent assay) while pGlu Aβ1‐42 was measured by ELISA. Hepatic mRNA expression levels of genes involved in cholesterol efflux and lipid metabolism were determined by quantitative real time polymerase chain reaction (qRT‐PCR).ResultT2D induced increased concentrations of plasma cholesterol as well as AST and ALT levels. The magnitudes, however, were dependent on sex and genotype and were statistically significant in female wild‐type mice, while a similar pattern was observed in APPxhQC transgenes. These increased plasma concentrations were accompanied by a down‐regulation of hepatic gene expression levels of LRP1, ABCA1, PPARα, PBC1β, and NEP that were statistically significant in female wild‐type mice, while a similarly pattern was observed in APPxhQC transgenic mice. More interestingly, T2D provoked a progressive shift of brain Aβ 1‐38 and 1‐40 from soluble to insoluble forms in male APPxhQC mice and a significant increase of pyroglutamate modified Aβ 1‐42 in female mice.ConclusionT2D in APPxhQC mice provokes a shift from soluble to large insoluble polymers of Aβ in the brain, corroborates the deteriorating role of T2D in the progression of AD