The BACE1 inhibitor LY2886721 improves diabetic phenotypes of BACE1 knock-in mice

Aim: The beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) has been identified as the central initiator of amyloid beta (A beta) generation in the brain, the key hallmark of Alzheimer's disease (AD). However, recent studies provided evidence that BACE1 also plays a crucial role in metabolic regulation, and we have shown that neuronal human BACE1 knock-in mice (PLB4) display type 2 diabetes mellitus (T2DM)-like symptoms alongside AD-like impairments. Hence, we here investigated if targeted BACE1 inhibition using LY2886721, an active site BACE1 inhibitor, would improve glucose homeostasis, insulin sensitivity and motor performance in PLB4 mice. Materials and methods: LY2886721 was administered as a dietary supplement (0.02% wt/wt) for six consecutive weeks. Physiological, metabolic and motor assessments were performed during the last two weeks of treatment, followed by molecular tissue analyses post-mortem. Results: LY2886721 treatment improved glucose homeostasis and hepatic gluconeogenesis in diabetic PLB4 mice, as determined by improvements in basal glucose and glucose/pyruvate tolerance tests. Furthermore, LY2886721 improved hepatic insulin sensitivity, as indicated by enhanced basal hyperphosphorylation of insulin receptors. In PLB4 brains, we detected altered basal conditions of APP expression and processing, with beneficial effects on APP processing achieved by LY2886721 treatment. No improvements in motor coordination were found. Conclusions: Our data provide support for a role of BACE1 as a regulator of systemic glucose homeostasis and suggest BACE1 inhibitors for the treatment of T2DM-associated pathologies, especially in cases where diabetes is comorbid to AD.

Automated summary

The study demonstrates the role of BACE1 in regulating systemic glucose homeostasis and suggests BACE1 inhibitors for treating T2DM-associated pathologies. LY2886721 treatment improved glucose homeostasis and hepatic insulin sensitivity in PLB4 mice, but did not show improvements in motor coordination.