title: The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice.
abstract: Neurodegenerative tauopathies, such as Alzheimer's disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a transgenic model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Jenna
authors.initials: J
authors.lastname: Carroll
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Yuemang
authors.initials: Y
authors.lastname: Yao
authors.forename: Michiyo
authors.initials: M
authors.lastname: Iba
authors.forename: Justin S
authors.initials: JS
authors.lastname: Potuzak
authors.forename: Anne-Marie L
authors.initials: AM
authors.lastname: Hogan
authors.forename: Sharon X
authors.initials: SX
authors.lastname: Xie
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Brunden
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000473:pathology / Q000523:psychology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D034261:Epothilones / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000187:drug effects / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000473:pathology / Q000523:psychology; D024801:Tauopathies / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D050257:Tubulin Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D016875:tau Proteins / Q000235:genetics
chemical_list: D034261:Epothilones; D050257:Tubulin Modulators; D016875:tau Proteins; C114026:desoxyepothilone B