>>Protein Inhibitor Tangles with Alzheimer's Disease

Tampa, FL (Feb. 15, 2007) -- Researchers have shown that a drug that inhibits the function of the protein Hsp90 reduces brain levels in mice of the protein tau, the abnormal accumulation of which has been implicated in the development of Alzheimer's disease. The study appears online Feb.15 in advance of its publication in the March issue of the Journal of Clinical Investigation.

"The study describes the potential for a completely new type of drug in the fight against Alzheimer's disease," said lead author Chad Dickey, PhD, assistant professor in Molecular Pharmacology and Physiology at the University of South Florida College of Medicine. Dr. Dickey conducted the research while he worked for the Mayo Clinic in Jacksonville, FL, and continues his investigation of proteins that may serve as new drug targets for Alzheimer's.

A hallmark of Alzheimer's disease is the abnormal accumulation of phosphorylated tau (p-tau) proteins resulting in the formation of neurofibrillary tangles that impair brain axons, which conduct nerve impulses. Enhancing removal of these p-tau proteins may therefore be a relevant treatment strategy.

In the study, Dr. Dickey, Leonard Petrucelli, PhD, and colleagues from the Mayo Clinic showed that a complex of two proteins, CHIP and Hsp90 (which are involved in protein refolding and degradation), plays a role in alleviating p-tau accumulation in mice and cultured human cells. They went on to show that administering an Hsp90 inhibitor, EC102, to mice overexpressing human tau caused a significant reduction in p-tau levels.

Hsp90 is known as a "chaperone" protein that, while trying to repair other damaged proteins in the brain, may actually prevent their degradation. One such damaged protein is the tau protein that accumulates in the Alzheimer's brain and is linked to memory loss.

"Hsp90 inhibitors could in essence force the degradation of the damaged tau protein, clearing it from the brain," Dr. Dickey said. "Moreover, this drug may be able to specifically target only the affected areas in the human brain, resulting in much fewer side effects."

The findings suggest a pivotal role for Hsp90 in aberrant tau degradation and potentially in tau refolding. Unlike many drugs, EC102 is able to cross the blood-brain barrier, making it a highly promising therapeutic candidate for Alzheimer's and other conditions in which tau accumulates in excess in the brain.