Acylpeptide hydrolase (ACPH), a serine protease present in the central nervous system (CNS), is believed to have a function in modulating synaptic plasticity, cleavage of beta amyloid peptide and degradation of aggregated oxidized proteins. In this report, we demonstrate for the first time the presence of ACPH in the synapse and its preferential localization at the pre-synaptic side. We isolated subcellular fractions from the rat telencephalon enriched in pre- versus post-synaptic components by using differential centrifugation steps to evaluate ACPH catalytic activity and expression level. Relative ACPH levels were determined by Western blot techniques while antibodies against synaptophysin and PSD-95 were used as positive pre- and post-synaptic markers, respectively. Our results show that ACPH protein levels are significantly increased at the synapse, which correlates with a 56% increase in ACPH activity. Furthermore, Western blot experiments show that ACPH is preferentially located at the pre-synaptic side and this is consistent with the increase of its enzymatic activity in fractions enriched in pre-synaptic components. These results give new insights regarding the localization and a putative role of ACPH in the CNS. (c) 2012 Elsevier Ireland Ltd. All rights reserved.The authors are indebted to the following funding grants: Programa Bicentenario en Ciencia y Tecnologia (No PSD-11) to R.S. and F.P.; VRIDT funding grant from Universidad Catolica del Norte to R.S. and F.P.; Fondecyt No 1100322 and Proyecto Anillo ACT09-06 to U.W. Fondef D0911057 to R.S and F.P.3FONDEFrsandoval@ucn.cl; uwyneken@uandes.cl; pancetti@ucn.clPrograma Bicentenario en Ciencia y Tecnologia [PSD-11]; Universidad Catiilica del Norte; Fondecyt [1100322]; Proyecto Anillo [ACT09-06]; Fondef [D0911057]FONDEF