Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Biochim Biophys Acta Mol Basis Dis. 2021 Jul 1;1867(7):166149. doi: 10.1016/j.bbadis.2021.166149. Epub 2021 Apr 20.
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.
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.
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.
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.
β-位淀粉样前体蛋白（APP）裂解酶 1（BACE1）已被确定为大脑中淀粉样β（Aβ）生成的中心启动子，是阿尔茨海默病（AD）的关键标志。然而，最近的研究提供了证据表明，BACE1 还在代谢调节中发挥着至关重要的作用，我们已经表明，神经元人 BACE1 敲入小鼠（PLB4）表现出 2 型糖尿病（T2DM）样症状以及 AD 样损伤。因此，我们在这里研究了使用 LY2886721（一种活性位点 BACE1 抑制剂）靶向 BACE1 抑制是否会改善 PLB4 小鼠的葡萄糖稳态、胰岛素敏感性和运动表现。
LY2886721 作为膳食补充剂（0.02%wt/wt）连续给药 6 周。在治疗的最后两周进行生理、代谢和运动评估，然后在死后进行分子组织分析。
LY2886721 治疗改善了糖尿病 PLB4 小鼠的葡萄糖稳态和肝糖异生，通过改善基础葡萄糖和葡萄糖/丙酮酸耐量试验来确定。此外，LY2886721 改善了肝胰岛素敏感性，表现为胰岛素受体的基础过度磷酸化增强。在 PLB4 大脑中，我们检测到 APP 表达和加工的基础条件发生改变，LY2886721 治疗对 APP 加工有有益影响。未发现运动协调能力有任何改善。
我们的数据为 BACE1 作为全身葡萄糖稳态调节剂的作用提供了支持，并表明 BACE1 抑制剂可用于治疗与 T2DM 相关的病理，特别是在糖尿病与 AD 共病的情况下。
