title: Targeting Hsp90 and its co-chaperones to treat Alzheimer's disease.
abstract: BACKGROUND
  Alzheimer's disease, characterized by the accumulation of hyperphosphorylated tau and β amyloid (Aβ), currently lacks effective treatment. Chaperone proteins, such as the heat shock protein (Hsp) 90, form macromolecular complexes with co-chaperones, which can regulate tau metabolism and Aβ processing. Although small molecule inhibitors of Hsp90 have been successful at ameliorating tau and Aβ burden, their development into drugs to treat disease has been slow due to the off- and on-target effects of this approach as well as challenges with the pharmacology of current scaffolds. Thus, other approaches are being developed to improve these compounds and to target co-chaperones of Hsp90 in an effort to limit these liabilities.
  
  
  METHODS
  This article discusses the most current developments in Hsp90 inhibitors including advances in blood-brain barrier permeability, decreased toxicity and homolog-specific small-molecule inhibitors. In addition, we discuss current strategies targeting Hsp90 co-chaperones rather than Hsp90 itself to reduce off-target effects.
  
  
  CONCLUSIONS
  Although Hsp90 inhibitors have proven their efficacy at reducing tau pathology, they have yet to meet with success in the clinic. The development of Hsp90/tau complex-specific inhibitors and further development of Hsp90 co-chaperone-specific drugs should yield more potent, less toxic therapeutics.
authors: University of South Florida, USF Health Byrd Institute, Department of Molecular Medicine , 4001 E. Fletcher Avenue, Tampa, FL 33613 , USA.
authors: Laura J
authors: LJ
authors: Blair
authors: Jonathan J
authors: JJ
authors: Sabbagh
authors: Chad A
authors: CA
authors: Dickey
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D058990:Molecular Targeted Therapy; D016875:tau Proteins / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D016875:tau Proteins
keywords: Alzheimer’s disease; chaperone; co-chaperone; heat shock protein 90; heat shock protein 90 inhibitors; peptidyl-prolyl isomerase; tau; tetratricopeptide; β amyloid