The researchers say their findings provide a potential therapeutic strategy for treating these diseases. The study will appear online Feb.15 in advance of publication in the March issue of the Journal of Clinical Investigation.
Aggregation of abnormal tau is one of the pathologic hallmarks of a group of neurodegenerative disorders called tauopathies, which includes Alzheimer\’s disease. Many researchers believe once tau aggregates to form NFTs, brain damage and resulting dementia may be irreversible, and they hope that disrupting the aggregation processes will lead to better treatments.
Mayo Clinic molecular neuroscientist Leonard Petrucelli, Ph.D., and his colleagues genetically and pharmacologically manipulated a system inside cells called the chaperone complex to inhibit heat shock factor protein 90 (Hsp90), one of many molecules in the chaperone complex. The complex acts, as its name suggests, as an escort system for abnormal or misfolded proteins, targeting them for either "correction" or "degradation." If the chaperone complex attempts a correction, but can not properly refold a substrate, the protein will then be targeted for degradation.
Petrucelli\’s group was the first to demonstrate that when the protein refolding pathway is blocked, it dramatically accelerates the degradation pathway in cell culture systems. In this study, Petrucelli blocked the refolding pathway in cell culture by silencing Hsp90 co-chaperone molecules critical to the refolding pathway through a process called RNA interference.
Petrucelli then gave mice that were genetically engineered to contain the human tau gene an Hsp90 inhibitor called EC102 that his colleagues identified as a compound that inhibits Hsp90 in brain. These experiments demonstrated that when EC102 was given, it selectively inhibited the action of Hsp90 and increased degradation of abnormal tau proteins in these transgenic mice. Further, when the researchers looked in areas of the brain most affected by Alzheimer\’s disease, they observed that the Hsp90/degradation complex is present in a high affinity state compared to unaffected brain regions and control brain. "This data shows that although Hsp90 levels are the same between the cortex area, which is affected, and the cerebellum, which isn\’t, the protein isn\’t behaving in the same manner," Petrucelli says. "It demonstrates that areas of the brain that show a lot of Alzheimer\’s-associated pathology are sensing the presence of abnormal protein."
Petrucelli says this directed activity of EC102 is encouraging from a drug development point of view. "The challenge will be if other substrates are targeted by this approach," he says. "Experimental compounds might have multiple targets so you might have multiple responses that result in unwanted side effects," he says. But Petrucelli adds that this doesn\’t seem to be happening. "We looked at other proteins that are degraded by this compound, and they\’re not changed. So it is only acting on proteins that are abnormally accumulating in the affected areas."
As a next step, Petrucelli wants to conduct dosing experiments with a mouse model where tau expression can be turned on and off and treat these mice at specific intervals of developing tau pathology and memory deficits. He speculates the optimal time to begin drug therapy may be before the degradation system, which acts like a cellular garbage can, gets too full and can\’t cope with any more abnormal tau.
This work was supported by grants from the Mayo Foundation and the Institute for Study of Aging.