Obesity is linked to neurodegenerative diseases through neuroinflammation. Pleiotrophin (PTN) is a cytokine that is upregulated in different neuroinflammatory disorders of diverse origin. PTN is a ligand and an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. To investigate the role of RPTP β/ζ, in neuroinflammation and neurodegeneration, we used the APP/PS1 genetic model of Alzheimer disease (AD) and a high-fat diet (HFD)-induced obesity model. Three-month-old wild type (WT) mice were fed with standard chow or HFD (60 Kcal % fat) for three months. MY10, an exogenous RPTPβ/ζ inhibitor was administered intragastrically at different doses (60 mg/kg and 90 mg/kg). First, we determined that HFD increased TAU and phospho-TAU levels in WT mice, associated with sporadic AD. HFD produced long-term memory loss in the novel object recognition test and MY10 potentiated these effects on cognition, exacerbating short- and long-term memory loss. Moreover, MY10 treatment increased adult hippocampal neurogenesis, which was enhanced by HFD, potentially contributing to HFD deleterious cognitive effects. In the APP/PS1 AD model, increased PTN levels in the brain were observed, suggesting that PTN overexpression takes part of a neurotrophic response in this genetic model of AD. To test this hypothesis, we studied the effect of MY10 in this model. Treatment with the higher dose of MY10 (90 mg/kg) significantly reduced the number of Ab plaques in 8-10 month-old male mice, not in females, suggesting that RPTPβ/ζ plays an important role modulating Aβ plaque formation in a sex-specific manner.