title: Heat shock protein 70 prevents both tau aggregation and the inhibitory effects of preexisting tau aggregates on fast axonal transport.
abstract: Aggregation and accumulation of the microtubule-associated protein tau are associated with cognitive decline and neuronal degeneration in Alzheimer's disease and other tauopathies. Thus, preventing the transition of tau from a soluble state to insoluble aggregates and/or reversing the toxicity of existing aggregates would represent a reasonable therapeutic strategy for treating these neurodegenerative diseases. Here we demonstrate that molecular chaperones of the heat shock protein 70 (Hsp70) family are potent inhibitors of tau aggregation in vitro, preventing the formation of both mature fibrils and oligomeric intermediates. Remarkably, addition of Hsp70 to a mixture of oligomeric and fibrillar tau aggregates prevents the toxic effect of these tau species on fast axonal transport, a critical process for neuronal function. When incubated with preformed tau aggregates, Hsp70 preferentially associated with oligomeric over fibrillar tau, suggesting that prefibrillar oligomeric tau aggregates play a prominent role in tau toxicity. Taken together, our data provide a novel molecular basis for the protective effect of Hsp70 in tauopathies.
authors: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States. k-patterson@md.northwestern.edu
authors: Kristina R
authors: KR
authors: Patterson
authors: Sarah M
authors: SM
authors: Ward
authors: Benjamin
authors: B
authors: Combs
authors: Kellen
authors: K
authors: Voss
authors: Nicholas M
authors: NM
authors: Kanaan
authors: Gerardo
authors: G
authors: Morfini
authors: Scott T
authors: ST
authors: Brady
authors: T Chris
authors: TC
authors: Gamblin
authors: Lester I
authors: LI
authors: Binder
mesh_terms: D001370:Axonal Transport; D015536:Down-Regulation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D058105:Polymerization; D011485:Protein Binding; D024801:Tauopathies / Q000378:metabolism*; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D016875:tau Proteins