Pharmacological PTP1B inhibition rescues motor learning, neuroinflammation, and hyperglycaemia in a mouse model of Alzheimer’s Disease

Background
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 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 (PLBWT) controls.
Methods
Five-month-old male PLB4 and PLBWT 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.
Results
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, and decreased insulin receptor substrate-1 (IRS1) and dipeptidyl peptidase-4 (DPP4) proteins in the liver.
Conclusion
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.