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The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins.

A primary pathologic component of Alzheimer's disease (AD) is the formation of neurofibrillary tangles composed of hyperphosphorylated tau (p-tau). Expediting the removal of these p-tau species may be a relevant therapeutic strategy. Here we report that inhibition of Hsp90 led to decreases in p-tau levels independent of heat shock factor 1 (HSF1) activation. A critical mediator of this mechanism was carboxy terminus of Hsp70-interacting protein (CHIP), a tau ubiquitin ligase. Cochaperones were also involved in Hsp90-mediated removal of p-tau, while those of the mature Hsp90 refolding complex prevented this effect. This is the first demonstration to our knowledge that blockade of the refolding pathway promotes p-tau turnover through degradation. We also show that peripheral administration of a novel Hsp90 inhibitor promoted selective decreases in p-tau species in a mouse model of tauopathy, further suggesting a central role for the Hsp90 complex in the pathogenesis of tauopathies. When taken in the context of known high-affinity Hsp90 complexes in affected regions of the AD brain, these data implicate a central role for Hsp90 in the development of AD and other tauopathies and may provide a rationale for the development of novel Hsp90-based therapeutic strategies.

Pubmed ID: 17304350


  • Dickey CA
  • Kamal A
  • Lundgren K
  • Klosak N
  • Bailey RM
  • Dunmore J
  • Ash P
  • Shoraka S
  • Zlatkovic J
  • Eckman CB
  • Patterson C
  • Dickson DW
  • Nahman NS
  • Hutton M
  • Burrows F
  • Petrucelli L


The Journal of clinical investigation

Publication Data

March 2, 2007

Associated Grants

  • Agency: NIA NIH HHS, Id: P01-AG17216
  • Agency: NINDS NIH HHS, Id: P50-NS40256

Mesh Terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease
  • Animals
  • Blood-Brain Barrier
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Female
  • HSP90 Heat-Shock Proteins
  • Humans
  • Male
  • Mice
  • Molecular Chaperones
  • Phosphorylation
  • Protein Folding
  • RNA, Small Interfering
  • Serine
  • Tauopathies
  • Transcription Factors
  • Ubiquitin-Protein Ligases
  • tau Proteins