Amyloid β-Peptide Effects on Glucose Regulation Are Dependent on Apolipoprotein E Genotype

Abstract

The apolipoprotein E gene (APOE) confers the greatest genetic risk factor for Alzheimer’s disease (AD), wherein the «4 allele confers an elevated risk compared with the « 3 allele. Biological mechanisms that differ across these alleles have been explored in mouse models wherein the murine Apoe gene has undergone targeted replacement with sequences encoding human ApoE3 or ApoE4 (ApoE-TR mice). Such models have indicated that the two variants of ApoE produce differential effects on energy metabolism, including metabolic syn-drome. However, glucose regulation has not been compared in ApoE-TR mice with and without amyloid b-peptide (Aβ) accumulation. We crossed ApoE3-TR and ApoE4-TR mice with a transgenic line that accumu-lates human Aβ1-42. In male ApoE3-TR mice, introduction of Aβ caused aberrations in glucose tolerance and in membrane translocation of astrocytic glucose transporter 1 (GLUT1). Phosphorylation of Tau at AD-relevant sites was correlated with glucose intolerance. These effects appeared independent of insulin dysregulation and were not observed in females. In ApoE4-TR mice, the addition of Aβ had no significant effects because of a trend toward perturbation of the baseline values.