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Journal article
Allosteric Heat Shock Protein 70 Inhibitors Rapidly Rescue Synaptic Plasticity Deficits by Reducing Aberrant Tau
Biological psychiatry (1969), v 74(5), pp 367-374
01 Sep 2013
PMID: 23607970
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The microtubule-associated protein tau accumulates in neurodegenerative diseases known as tauopathies, the most common being Alzheimer’s disease. One way to treat these disorders may be to reduce abnormal tau levels through chaperone manipulation, thus subverting synaptic plasticity defects caused by tau’s toxic accretion.
Tauopathy models were used to study the impact of YM-01 on tau. YM-01 is an allosteric promoter of triage functions of the most abundant variant of the heat shock protein 70 (Hsp70) family in the brain, heat shock cognate 70 protein (Hsc70). The mechanisms by which YM-01 modified Hsc70 activity and tau stability were evaluated with biochemical methods, cell cultures, and primary neuronal cultures from tau transgenic mice. YM-01 was also administered to acute brain slices of tau mice; changes in tau stability and electrophysiological correlates of learning and memory were measured.
Tau levels were rapidly and potently reduced in vitro and ex vivo upon treatment with nanomolar concentrations of YM-01. Consistent with Hsc70 having a key role in this process, overexpression of heat shock protein 40 (DNAJB2), an Hsp70 co-chaperone, suppressed YM-01 activity. In contrast to its effects in pathogenic tauopathy models, YM-01 had little activity in ex vivo brain slices from normal, wild-type mice unless microtubules were disrupted, suggesting that Hsc70 acts preferentially on abnormal pools of free tau. Finally, treatment with YM-01 increased long-term potentiation in tau transgenic brain slices.
Therapeutics that exploit the ability of chaperones to selectively target abnormal tau can rapidly and potently rescue the synaptic dysfunction that occurs in Alzheimer’s disease and other tauopathies.
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Details
- Title
- Allosteric Heat Shock Protein 70 Inhibitors Rapidly Rescue Synaptic Plasticity Deficits by Reducing Aberrant Tau
- Creators
- Jose Abisambra - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaUmesh K. Jinwal - Department of Pharmaceutical Sciences, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaYoshinari Miyata - University of MichiganJustin Rogers - Department of Molecular Pharmacology and Physiology, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaLaura Blair - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaXiaokai Li - University of MichiganSandlin P. Seguin - University of PittsburghLi Wang - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaYing Jin - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaJustin Bacon - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaSarah Brady - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaMatthew Cockman - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaChantal Guidi - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaJuan Zhang - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaJohn Koren - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaZapporah T. Young - University of MichiganChristopher A. Atkins - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaBo Zhang - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaLisa Y. Lawson - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaEdwin J. Weeber - Department of Molecular Pharmacology and Physiology, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FloridaJeffrey L. Brodsky - University of PittsburghJason E. Gestwicki - University of MichiganChad A. Dickey - Department of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, Florida
- Publication Details
- Biological psychiatry (1969), v 74(5), pp 367-374
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000324050500010
- Scopus ID
- 2-s2.0-84882250523
- Other Identifier
- 991020545410504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences
- Psychiatry