Neuronal Protection by a Novel C-terminal Hsp90 Modulator

Alzheimer's disease (AD), like most neurodegenerative disorders, is characterized by accumulation of misfolded and aggregated proteins, indicating that the protein quality control machinery is compromised. Enhancing the activity of molecular chaperones such as the `heat shock' proteins (Hsp's) that re-fold or signal degradation of damaged proteins may help remove protein oligomers/aggregates and prevent cell death. The goal of our studies was to characterize a novel, non-toxic Hsp90 modulator, KU-32, which protects primary cortical neurons against Aβ1-42, a toxic peptide found in AD brain. Pharmacokinetic studies indicated that KU-32 is blood brain barrier permeable and orally bioavailable. Using two AD mouse models, JNPL3 and rTg4510, which both contain the P301L Tau mutation and develop aberrant Tau tangles as well as cognitive impairments, we assessed KU-32 treatment in vivo. The JNPL3 mice were treated with 20 mg/kg of KU-32 or with 12.5% Captisol® (vehicle) five times a week for six months. Immunohistochemical studies indicated significant decreases of hyperphosphorylated Tau in the cortical region. The rTg4510 mice were treated with 60 mg/kg of KU-32 or with vehicle (5% Captisol®) twice a week for 10 weeks. Immunofluorescent analyses demonstrated significant protection against dendritic pathology and neuronal death in KU-32-treated vs vehicle-treated rTg4510 mice. Further studies were conducted to examine the potential mechanisms of drug action. We hypothesized that KU-32 activated the heat shock response leading to an increase in molecular chaperones involved in protein quality control such as Hsp70. Our data suggest that KU-32 is not acting through this mechanism, and further studies are needed to elucidate the mechanism. Overall, our in vivo results suggest that the novel Hsp90 modulator, KU-32, may have therapeutic potential for treatment of AD.

Grantor dc:publisher

University of Kansas

Year dc:date.issued

2012

Author dc:creator

• Menchen, Heather Ann

Advisor dc:contributor.advisor

• Michaelis, Mary L

• Pharmacology
• Alzheimer's disease
• Hsp90
• Neurofibrillary tangle
• Tau

Statement dc:rights

• This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.

Language dc:language.iso

en

Dc Identifier Other

http://dissertations.umi.com/ku:12291

OAI identifier oai:identifier

oai:kuscholarworks.ku.edu:1808/10216