Abstract
The apolipoprotein E gene (APOE) constitutes the greatest genetic risk factor for Alzheimer’s disease, wherein the ε4 allele confers a dramatically elevated risk compared to the more common ε3 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 Aβ accumulation. We crossed ApoE3- and ApoE4-TR mice with a transgenic line that accumulates human Aβ1-42. In male ApoE3-TR mice, introduction of Aβ 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 Aβ 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 ε4 allele. The fact that ApoE4 generally failed to exacerbate the effects of Aβ on glucose further highlights the growing distinction between the glycemic effects of Aβ versus those of peripheral insulin resistance.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of interest statement: The authors declare no competing financial interests.
