title: Aβ-mediated spine changes in the hippocampus are microtubule-dependent and can be reversed by a subnanomolar concentration of the microtubule-stabilizing agent epothilone D.
abstract: Dendritic spines represent the major postsynaptic input of excitatory synapses. Loss of spines and changes in their morphology correlate with cognitive impairment in Alzheimer's disease (AD) and are thought to occur early during pathology. Therapeutic intervention at a preclinical stage of AD to modify spine changes might thus be warranted. To follow the development and to potentially interfere with spine changes over time, we established a long term ex vivo model from organotypic cultures of the hippocampus from APP transgenic and control mice. The cultures exhibit spine loss in principal hippocampal neurons, which closely resembles the changes occurring in vivo, and spine morphology progressively changes from mushroom-shaped to stubby. We demonstrate that spine changes are completely reversed within few days after blocking amyloid-β (Aβ) production with the gamma-secretase inhibitor DAPT. We show that the microtubule disrupting drug nocodazole leads to spine loss similar to Aβ expressing cultures and suppresses DAPT-mediated spine recovery in slices from APP transgenic mice. Finally, we report that epothilone D (EpoD) at a subnanomolar concentration, which slightly stabilizes microtubules in model neurons, completely reverses Aβ-induced spine loss and increases thin spine density. Taken together the data indicate that Aβ causes spine changes by microtubule destabilization and that spine recovery requires microtubule polymerization. Moreover, our results suggest that a low, subtoxic concentration of EpoD is sufficient to reduce spine loss during the preclinical stage of AD.
authors.affiliation: Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076 Osnabrück, Germany.
authors.forename: Lorène
authors.initials: L
authors.lastname: Penazzi
authors.affiliation: Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076 Osnabrück, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Tackenberg
authors.affiliation: Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076 Osnabrück, Germany.
authors.forename: Adnan
authors.initials: A
authors.lastname: Ghori
authors.affiliation: Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076 Osnabrück, Germany.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Golovyashkina
authors.affiliation: Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076 Osnabrück, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Niewidok
authors.affiliation: Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076 Osnabrück, Germany.
authors.forename: Karolin
authors.initials: K
authors.lastname: Selle
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, United States; Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076 Osnabrück, Germany.
authors.forename: Lidia
authors.initials: L
authors.lastname: Bakota
authors.affiliation: Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076 Osnabrück, Germany. Electronic address: brandt@biologie.uni-osnabrueck.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Brandt
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects* / Q000473:pathology*; D003959:Diamines / Q000494:pharmacology; D034261:Epothilones / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015739:Nocodazole / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: C000612000:24-diamino-5-phenylthiazole; D016564:Amyloid beta-Protein Precursor; D003959:Diamines; D034261:Epothilones; D013844:Thiazoles; D050257:Tubulin Modulators; D015739:Nocodazole; C114026:desoxyepothilone B
keywords: Alzheimer's disease; Amyloid beta; Dendritic spine; Epothilone; Microtubules