A non-toxic Hsp90 inhibitor protects neurons from Abeta-induced toxicity.
The molecular chaperones have been implicated in numerous neurodegenerative disorders in which the defining pathology is misfolded proteins and the accumulation of protein aggregates. In Alzheimer's disease, hyperphosphorylation of tau protein results in its dissociation from microtubules and the formation of pathogenic aggregates. An inverse relationship was demonstrated between Hsp90/Hsp70 levels and aggregated tau, suggesting that Hsp90 inhibitors that upregulate these chaperones could provide neuroprotection. We recently identified a small molecule novobiocin analogue, A4 that induces Hsp90 overexpression at low nanomolar concentrations and sought to test its neuroprotective properties. A4 protected neurons against Abeta-induced toxicity at low nanomolar concentrations that paralleled its ability to upregulate Hsp70 expression. A4 exhibited no cytotoxicity in neuronal cells at the highest concentration tested, 10 microM, thus providing a large therapeutic window for neuroprotection. In addition, A4 was transported across BMECs in vitro, suggesting the compound may permeate the blood-brain barrier in vivo. Taken together, these data establish A4, a C-terminal inhibitor of Hsp90, as a potent lead for the development of a novel class of compounds to treat Alzheimer's disease.
Ansar
Sabah
S
Department of Pharmacology and Toxicology, The University of Kansas, Malott 5064, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7563, USA.
Burlison
Joseph A
JA
Hadden
M Kyle
MK
Yu
Xiao Ming
XM
Desino
Kelly E
KE
Bean
Jennifer
J
Neckers
Len
L
Audus
Ken L
KL
Michaelis
Mary L
ML
Blagg
Brian S J
BS
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000166:cytology; D002417:Cattle; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008833:Microcirculation / Q000473:pathology; D008956:Models, Chemical; D008968:Molecular Conformation; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents