RECEPTOR PROTEIN TYROSINE PHOSPHATASE (RPTP) Β/Ζ MODULATES PERINEURONAL NETS AND PARVALBUMIN INTERNEURONS IN THE HIPPOCAMPUS OF APP/PS1 MICE

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and synaptic dysfunction in the hippocampus. Perineuronal nets (PNNs), specialized extracellular matrix structures that predominantly surround parvalbumin (PV)-expressing GABAergic interneurons, are critical for synaptic plasticity, and are known to be disrupted in AD. One of the components of PNNs, the receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ) is also known to modulate Aβ plaque formation. In this study, we investigated the effects of pharmacological RPTPβ/ζ inhibition on PNNs organization and PV+ interneurons in the hippocampal dorsal subiculum (DS) of wild-type (WT) and APP/PS1 mice, a transgenic mouse model of AD. Two experimental groups according to the duration (14 days or 3 months) of the treatment with MY10 (a selective RPTPβ/ζ inhibitor, 60 or 90 mg/kg) were studied. We found that treatment with MY10 modulates the number and intensity of hippocampal PNNs in a dose-, sex-, and genotype-dependent manner, independently of treatment duration. Notably, high-intensity PNNs were preserved in female APP/PS1 mice after short treatment. Furthermore, MY10 treatment dramatically increases the number of PV+ cells in the DS of WT mice compared with APP/PS1 mice. Analyses of hippocampal gene expression revealed that MY10 treatment had differential effects on PNN components. Specifically, the expression of Aggrecan was affected by both short- and long-term MY10 treatment. Overall, these findings demonstrate that the inhibition of RPTPβ/ζ influences the integrity of PNNs and the stability of GABAergic interneuron in the hippocampus. This supports the importance of modulation of the brain extracellular matrix in the pathogenesis of AD.