title: Abnormal cortical lysosomal β-hexosaminidase and β-galactosidase activity at post-synaptic sites during Alzheimer's disease progression.
abstract: A critical role of endosomal-lysosomal system alteration in neurodegeneration is supported by several studies. Dysfunction of the lysosomal compartment is a common feature also in Alzheimer's disease. Altered expression of lysosomal glycohydrolases has been demonstrated not only in the brain and peripheral tissues of Alzheimer's disease patients, but also in presymptomatic subjects before degenerative phenomenon becomes evident. Moreover, the presence of glycohydrolases associated to the plasma membrane have been widely demonstrated and their alteration in pathological conditions has been documented. In particular, lipid microdomains-associated glycohydrolases can be functional to the maintenance of the proper glycosphingolipids pattern, especially at cell surface level, where they are crucial for the function of cell types such as neurons. In this study we investigated the localization of β-hexosaminidase and β-galactosidase glycohydrolases, both involved in step by step degradation of the GM1 to GM3 gangliosides, in lipid microdomains from the cortex of both an early and advanced TgCRND8 mouse model of Alzheimer's disease. Throughout immunoprecipitation experiments of purified cortical lipid microdomains, we demonstrated for the first time that β-hexosaminidase and β-galactosidase are associated with post-synaptic vesicles and that their activities are increased at both the early and the advanced stage of Alzheimer's disease. The early increase of lipid microdomain-associated β-hexosaminidase and β-galactosidase activities could have relevant implications for the pathophysiology of the disease since their possible pharmacological manipulation could shed light on new reliable targets and biological markers of Alzheimer's disease.
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06123 Perugia, Italy; Department of Medical and Biological Sciences (DSMB), University of Udine, P.le S. Maria della Misericordia 15, 33100 Perugia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Magini
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06123 Perugia, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Polchi
authors.affiliation: Deparment of Medicine, Neurological Clinic, University of Perugia, S. Maria della Misericordia Hospital, 06156 Perugia, Italy; IRCCS S. Lucia Foundation, 00143 Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06123 Perugia, Italy.
authors.forename: Brunella
authors.initials: B
authors.lastname: Tancini
authors.affiliation: Deparment of Medicine, Neurological Clinic, University of Perugia, S. Maria della Misericordia Hospital, 06156 Perugia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Tantucci
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06123 Perugia, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Urbanelli
authors.affiliation: IRCCS Institute for Pharmacological Research "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Borsello
authors.affiliation: Deparment of Medicine, Neurological Clinic, University of Perugia, S. Maria della Misericordia Hospital, 06156 Perugia, Italy; IRCCS S. Lucia Foundation, 00143 Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06123 Perugia, Italy; CEMIN-Center of Excellence for Innovative Nanostructured Material, Perugia, Italy. Electronic address: carla.emiliani@unipg.it.
authors.forename: Carla
authors.initials: C
authors.lastname: Emiliani
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000201:enzymology* / Q000378:metabolism; D006026:Glycoside Hydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008247:Lysosomes / Q000201:enzymology*; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism*
chemical_list: D006026:Glycoside Hydrolases; D001616:beta-Galactosidase
keywords: Alzheimer's disease; Membrane microdomains; Plasma membrane glycohydrolases