Franklin Zara, Hull Claire, Delibegovic Mirela, Platt Bettina
Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
Exp Neurol. 2025 Mar;385:115115. doi: 10.1016/j.expneurol.2024.115115. Epub 2024 Dec 11.
Patients with Alzheimer's Disease (AD) frequently suffer from comorbidities such as type 2 diabetes mellitus (T2DM), accompanied by shared common pathologies such as increased inflammation and impaired glucose homeostasis. Beta-secretase 1 (BACE1), the rate limiting enzyme in AD associated beta-amyloid (Aβ) production, is also implicated in metabolic dysfunction and can increase central and peripheral protein levels of protein tyrosine phosphatase 1B (PTP1B). PTP1B is a validated target in diabetes and obesity, and is a neuroinflammatory regulator involved in degenerative processes. This study investigated the effects of the PTP1B inhibitor, trodusquemine (MSI-1436) on the cognitive and metabolic phenotypes of the neuronal human BACE1 knock-in (PLB4) mouse, a co-morbidity model of AD and T2DM, and their wild-type (PLB) controls.
Five-month-old male PLB4 and PLB mice received PTP1B inhibitor treatment (1 mg/kg intraperitoneal injection; 5 weeks). Activity and spatial habituation (Phenotyper), motor learning (RotaRod), glucose tolerance, and brain and liver molecular analyses were analysed following treatment.
Inhibition of PTP1B improved motor learning alongside glucose tolerance in PLB4 mice, without affecting body weight/adiposity. MSI-1436 treatment led to lower protein levels of amyloid precursor protein (APP), reduced astrogliosis and restoration of the endoplasmic chaperone immunoglobulin heavy chain binding protein (BIP) in the brain, alongside decreased insulin receptor substrate-1 (IRS1) and dipeptidyl peptidase-4 (DPP4) proteins in the liver.
We provide evidence that neuronal BACE1 contributes to neuroinflammation and hyperglycaemia in PLB4 mice, and this can be partially rescued by PTP1B inhibition. Targeting PTP1B may therefore offer an attractive therapeutic approach to ameliorate co-morbidity associated pathologies in AD and T2DM.
阿尔茨海默病（AD）患者常伴有2型糖尿病（T2DM）等合并症，同时存在炎症增加和葡萄糖稳态受损等共同病理特征。β-分泌酶1（BACE1）是AD相关β-淀粉样蛋白（Aβ）生成的限速酶，也与代谢功能障碍有关，可增加蛋白酪氨酸磷酸酶1B（PTP1B）在中枢和外周的蛋白水平。PTP1B是糖尿病和肥胖症的一个已验证靶点，也是参与退行性过程的神经炎症调节因子。本研究调查了PTP1B抑制剂曲度喹明（MSI-1436）对神经元人BACE1基因敲入（PLB4）小鼠（AD和T2DM的合并症模型）及其野生型（PLB）对照的认知和代谢表型的影响。
5月龄雄性PLB4和PLB小鼠接受PTP1B抑制剂治疗（腹腔注射1mg/kg；5周）。治疗后分析活动和空间习惯化（表型分析器）、运动学习（转棒试验）、葡萄糖耐量以及脑和肝脏的分子分析。
抑制PTP1B可改善PLB4小鼠的运动学习能力和葡萄糖耐量，而不影响体重/肥胖。MSI-1436治疗导致脑内淀粉样前体蛋白（APP）水平降低、星形胶质细胞增生减少以及内质伴侣免疫球蛋白重链结合蛋白（BIP）恢复，同时肝脏中胰岛素受体底物-1（IRS1）和二肽基肽酶-4（DPP4）蛋白减少。
我们提供的证据表明，神经元BACE1在PLB4小鼠中导致神经炎症和高血糖，而PTP1B抑制可部分挽救这种情况。因此，靶向PTP1B可能为改善AD和T2DM相关合并症病理提供一种有吸引力的治疗方法。
