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

Ruta Dekeryte, Zara Franklin, Claire Hull, Lorenzo Croce, Sarah Kamli-Salino, Oliver Walter Helk, Philip Hoffmann, Zhixiang Yang, Gernot Riedel, Mirela Delibegovic, Bettina Platt* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Aim: The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) has been identified as the central initiator of amyloid β (Aβ) 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 motorassessments 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 yperphosphorylation 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 T2DMassociated pathologies, especially in cases where diabetes is comorbid to AD
Original languageEnglish
Article number166149
JournalBiochimica et Biophysica Acta. Molecular Basis of Disease : BBA
Volume1867
Issue number7
Early online date20 Apr 2021
DOIs
Publication statusE-pub ahead of print - 20 Apr 2021

Keywords

  • AD
  • T2DM
  • BACE1
  • LY2886721
  • Beta Amyloid

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