title: Beta-amyloid 1-42 monomers, but not oligomers, produce PHF-like conformation of Tau protein.
abstract: The mechanistic relationship between amyloid β1-42 (Aβ1-42) and the alteration of Tau protein are debated. We investigated the effect of Aβ1-42 monomers and oligomers on Tau, using mice expressing wild-type human Tau that do not spontaneously develop Tau pathology. After intraventricular injection of Aβ1-42, mice were sacrificed after 3 h or 4 days. The short-lasting treatment with Aβ monomers, but not oligomers, showed a conformational PHF-like change of Tau, together with hyperphosphorylation. The same treatment induced increase in concentration of GSK3 and MAP kinases. The inhibition of the kinases rescued the Tau changes. Aβ monomers increased the levels of total Tau, through the inhibition of proteasomal degradation. Aβ oligomers reproduced all the aforementioned alterations only after 4 days of treatment. It is known that Aβ1-42 monomers foster synaptic activity. Our results suggest that Aβ monomers physiologically favor Tau activity and dendritic sprouting, whereas their excess causes Tau pathology. Moreover, our study indicates that anti-Aβ therapies should be targeted to Aβ1-42 monomers too.
authors.affiliation: Department of Neuroscience, University of Torino, via Cherasco 15, 10126, Torino, Italy.|Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO), University of Torino, Regione Gonzole 10, 10043, Orbassano, Torino, Italy.|Unit of Geriatric Medicine, Department of Internal Medicine and Medical Specialties (DIMI), University of Genova, Viale Benedetto XV, 6, 16132, Genova, Italy.
authors.forename: Giusi
authors.initials: G
authors.lastname: Manassero
authors.affiliation: Department of Neuroscience, University of Torino, via Cherasco 15, 10126, Torino, Italy.|Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO), University of Torino, Regione Gonzole 10, 10043, Orbassano, Torino, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Guglielmotto
authors.affiliation: Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO), University of Torino, Regione Gonzole 10, 10043, Orbassano, Torino, Italy.
authors.forename: Raluca
authors.initials: R
authors.lastname: Zamfir
authors.affiliation: Unit of Geriatric Medicine, Department of Internal Medicine and Medical Specialties (DIMI), University of Genova, Viale Benedetto XV, 6, 16132, Genova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Borghi
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via Giuseppe La Masa, 19, 20156, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Colombo
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via Giuseppe La Masa, 19, 20156, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.affiliation: College of Sciences, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA.
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.affiliation: Unit of Geriatric Medicine, Department of Internal Medicine and Medical Specialties (DIMI), University of Genova, Viale Benedetto XV, 6, 16132, Genova, Italy.|IRCCS San Martino-IST, University of Genova, Viale Benedetto XV, 6, 16132, Genova, Italy.
authors.forename: Patrizio
authors.initials: P
authors.lastname: Odetti
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 West 168th Street, P&S 12-420D, New York, NY, 10032, USA.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.affiliation: Department of Neuroscience, University of Torino, via Cherasco 15, 10126, Torino, Italy.|Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO), University of Torino, Regione Gonzole 10, 10043, Orbassano, Torino, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tamagno
authors.affiliation: Unit of Geriatric Medicine, Department of Internal Medicine and Medical Specialties (DIMI), University of Genova, Viale Benedetto XV, 6, 16132, Genova, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Tabaton
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D066329:Protein Aggregates; D011487:Protein Conformation; D055503:Protein Multimerization; D012995:Solubility; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer's disease; MAPK; PHF; beta-amyloid; hTau mice; tau protein