The BACE1 inhibitor LY2886721 improves diabetic phenotypes of BACE1 knock-in mice,Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

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The BACE1 inhibitor LY2886721 improves diabetic phenotypes of BACE1 knock-in mice
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2021-04-20 , DOI: 10.1016/j.bbadis.2021.166149
Ruta Dekeryte ₁ , Zara Franklin ₁ , Claire Hull ₁ , Lorenzo Croce ₁ , Sarah Kamli-Salino ₁ , Oliver Helk ₁ , Philip A Hoffmann ₁ , Zhixiang Yang ₂ , Gernot Riedel ₁ , Mirela Delibegovic ₁ , Bettina Platt ₁

Affiliation

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 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.

中文翻译：

BACE1 抑制剂 LY2886721 可改善 BACE1 基因敲入小鼠的糖尿病表型

目的

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蛋白 β (Aβ) 生成的中心启动子，这是阿尔茨海默病 (AD) 的关键标志。然而，最近的研究提供的证据表明 BACE1 在代谢调节中也起着至关重要的作用，我们已经证明神经元人类BACE1敲入小鼠 (PLB4) 显示出 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活性位点 BACE1 抑制剂 LY2886721 的靶向 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。

材料和方法

LY2886721 作为膳食补充剂 (0.02% wt/wt) 连续六周给药。在治疗的最后两周进行生理、代谢和运动评估，然后进行死后分子组织分析。

结果

LY2886721 治疗改善了糖尿病 PLB4 小鼠的葡萄糖稳态和肝脏糖异生，这通过基础葡萄糖和葡萄糖/丙酮酸耐受性测试的改善来确定。此外，LY2886721 改善了肝脏胰岛素敏感性，如胰岛素受体的基础过度磷酸化增强所表明的。在 PLB4 大脑中，我们检测到 APP 表达和加工的基础条件发生了改变，LY2886721 处理对 APP 加工产生了有益的影响。没有发现运动协调性的改善。