PTP1B INHIBITION BY INTRANASAL CLARAMINE ADMINISTRATION AMELIORATES COGNITIVE IMPAIRMENT IN APP/PS1 MICE

Protein tyrosine phosphatase 1B (PTP1B) has been implicated in insulin resistance and neuroinflammatory mechanisms linked to Alzheimer’s disease (AD), suggesting that PTP1B may act as a molecular link between metabolic dysfunction and neurodegeneration. Accordingly, PTP1B inhibition represents a promising therapeutic strategy. Here, we investigated whether chronic intranasal administration of the PTP1B inhibitor claramine confers neuroprotective and metabolic benefits in a transgenic AD mouse model.
APPswe/PS1dE9 (APP/PS1) and wild-type (WT) littermates received intranasal administration of claramine (1 mg/kg/day) or saline three times per week from 5 to 7 months of age. Cognitive performance was evaluated using behavioral tests, and metabolic function was assessed by glucose tolerance and insulin tolerance tests. Brains were collected for Golgi staining, immunohistochemistry, and complementary molecular analyses.
Our results show that intranasal administration of claramine was associated with improved in cognitive performance and glucose metabolism in APP/PS1 mice. At the brain level, PTP1B inhibition attenuated glial reactivity and ameliorated amyloid-related pathology, including reduced Aβ1–42 levels, while preserving synaptic architecture in both cortex and hippocampus. In addition, RT-qPCR analyses supported broader effects of claramine across AD-related molecular pathways.
These findings indicate that targeting PTP1B via intranasal administration influences both central and peripheral alterations at early stages of the disease in APP/PS1 mice. This work supports claramine as a feasible strategy to mitigate cognitive impairment by targeting metabolic dysfunction, neuroinflammation, amyloid pathology and synaptic alterations, highlighting PTP1B as a potential therapeutic target at the interface between metabolic dysregulation and neurodegeneration.