Pleiotrophin and receptor protein tyrosine phosphatase β/ζ as key modulators of high-fat diet-induced cognitive impairment and brain alterations

Metabolic disorders, such as obesity, are highly related to neurodegenerative diseases through neuroinflammation. Pleiotrophin (PTN) is a cytokine that is upregulated in various neuroinflammatory disorders. PTN is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. To investigate the role of PTN, a HFD-induced obesity model was used in Ptn genetically deficient (Ptn^-/-) mice. To investigate the role of RPTPβ/ζ, we administered the selective inhibitor of RPTPβ/ζ, MY10, while mice were fed with HFD. The data demonstrate that Ptn deletion protects against both HFD-induced obesity and HFD-induced memory loss, whereas pharmacological inhibition of RPTPβ/ζ produces the opposite effects. In addition, HFD induced astrogliosis and microgliosis. However, Ptn deletion led to the absence of these glial responses, whereas MY10 reversed HFD-induced microgliosis. Finally, we demonstrated that PTN/RPTPβ/ζ signaling is important for adult hippocampal neurogenesis (AHN), the formation and maintenance of perineuronal nets (PNNs), and is involved in the regulation of the effects of HFD in these processes. The data demonstrate a key role of the PTN/RPTPβ/ζ signaling pathway in the connection between obesity, cognitive decline, and the associated brain alterations. The data suggest therapeutic potential in treating brain injuries associated with metabolic disorders, including mild cognitive impairment and dementia, through pharmacological modulation of this pathway.