Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype

Abstract

The apolipoprotein E gene (APOE) constitutes the greatest genetic risk factor for Alzheimers disease, wherein the {varepsilon}4 allele confers a dramatically elevated risk compared to the more common {varepsilon}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 -4 (ApoE-TR mice). Results with such models have indicated that the two variants of ApoE produce differential effects on energy metabolism, including metabolic syndrome. However, glucose regulation has not been compared in ApoE-TR mice with and without A{beta} accumulation. We crossed ApoE3- and ApoE4-TR mice with a transgenic line that accumulates human A{beta}1-42. In male ApoE3-TR mice, introduction of A{beta} caused aberrations in glucose tolerance and membrane translocation of astrocytic glucose transporter 1. 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 A{beta} had no significant effects due to a trend toward perturbation of the baselines. Thus, metabolic changes may have a larger interaction with AD pathology and its consequences in individuals who do not carry an APOE {varepsilon}4 allele. The fact that ApoE4 generally failed to exacerbate the effects of A{beta} on glucose further highlights the growing distinction between the glycemic effects of A{beta} versus those of peripheral insulin resistance.