title: Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, 33613, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Abisambra
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Jinwal
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Miyata
authors.forename: Justin
authors.initials: J
authors.lastname: Rogers
authors.forename: Laura
authors.initials: L
authors.lastname: Blair
authors.forename: Xiaokai
authors.initials: X
authors.lastname: Li
authors.forename: Sandlin P
authors.initials: SP
authors.lastname: Seguin
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.forename: Justin
authors.initials: J
authors.lastname: Bacon
authors.forename: Sarah
authors.initials: S
authors.lastname: Brady
authors.forename: Matthew
authors.initials: M
authors.lastname: Cockman
authors.forename: Chantal
authors.initials: C
authors.lastname: Guidi
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Koren
authors.forename: Zapporah T
authors.initials: ZT
authors.lastname: Young
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Atkins
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Lawson
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Weeber
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brodsky
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D017774:Long-Term Potentiation; D051379:Mice; D008822:Mice, Transgenic; D011726:Pyridinium Compounds / Q000494:pharmacology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D018840:HSP70 Heat-Shock Proteins; D011726:Pyridinium Compounds; C586423:YM-01 compound; D016875:tau Proteins
keywords: Alzheimer’s disease; Hsc70; YM-01; chaperones; rhodacyanine; tau