Reducing PTP1B in the Hippocampus Protects Against Cognitive Decline in Prediabetes

The prevalence of prediabetes is increasing globally, driven by rising obesity rates. Prediabetes increases the risk of neurodegenerative diseases, which are linked by neuroinflammation. Protein tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. However, the role and underlying mechanisms of PTP1B in prediabetes-induced cognitive impairment remain poorly understood. Here, we observed elevated levels of PTP1B in the serum of individuals with obesity and prediabetes. In mouse model of obesity and prediabetes induced by a high-fat, high-sugar diet (HFHSD), the PTP1B level was significantly increased in the hippocampus, correlating with cognitive decline, microglial activation, and inflammatory response. In a series of mouse models with selective PTP1B deletion, the loss of PTP1B in the hippocampus, hippocampal neurons, and leptin receptor–expressing cells reversed impairments of hippocampal leptin synaptic signaling, synaptic ultrastructure and associated proteins, and cognitive function in HFHSD-fed prediabetic mice. In a palmitic acid-induced, prediabetic, hippocampal neuronal model, genetic knockout or pharmacological inhibition of PTP1B effectively restored synaptic signaling and neurite outgrowth. These findings underscore the critical role of hippocampal neuronal PTP1B in mediating impairments of synaptic signaling leading to cognitive decline in prediabetes and suggest its significant therapeutic potential in addressing neurodegeneration. ARTICLE HIGHLIGHTS The present study reveals a previously unknown molecular mechanism linking prediabetes to neurodegeneration, addressing a critical gap in understanding metabolic-neurological interplay. We investigated whether PTP1B mediates prediabetes-induced cognitive impairment. PTP1B impaired synaptic signaling and synaptic ultrastructure in hippocampal neurons, contributing to cognitive decline in prediabetes. PTP1B is a novel therapeutic target for prediabetes-associated neurodegeneration.