Alzheimer’s disease currently affects 5.3 million Americans — a number that increases every 70 seconds, according to the Alzheimer’s Association. In response, an ongoing Penn study — whose latest results were published in October in the Journal of Neuroscience — aims “to do something substantive and serious about this epidemic,” Institute on Aging Director and Center for Neurodegenerative Disease Research Co-Director John Trojanowski said.
According to CNDR Director Virginia Lee, age is the primary risk factor for Alzheimer’s. The aging of the baby boomer generation, Lee said, has led to an increase in media and scientific attention to the “emotionally and financially” burdensome disease. An estimate by the Alzheimer’s Association pins costs associated with Alzheimer’s care at $172 billion in 2010.
Trojanowski and Lee, the study’s senior authors, collaborated with CNDR Director of Drug Discovery Kurt Brunden and senior research investigator Bin Zhang to discover and test epothilone D, a compound that may lead to potential therapies for Alzheimer’s patients.
The study may have important pharmaceutical implications in research for the currently incurable disease, as it addresses therapies focusing on tau, a protein that mutates in Alzheimer’s patients.
“It’s like taking aspirin for pneumonia. It may reduce the fever, but what you really need is an antibiotic,” Trojanowski said. “What we have right now is a pretty weak aspirin for Alzheimer’s disease.”
Comparing neural microtubules to train tracks that transport cellular material, Trojanowski explained that tau fulfills the function of “cross-ties.”
“If those cross-ties are removed, the tracks buckle and the train runs off the track,” Trojanowski said. This forms tangles in the brain, which contribute to the neurodegenerative quality of Alzheimer’s.
In 2005, Penn researchers studied Taxol — an anti-cancer drug used to prevent cancer cells from dividing and multiplying — as an effective replacement for mutated tau in Alzheimer’s patients. However, Lee noted, the drug was not able to penetrate the blood-brain barrier.
“The brain is such a sacred place” in which only select chemicals can enter, Lee said. Through tests performed on mice, researchers discovered that epothilone D successfully penetrated the blood-brain barrier and served tau’s role in stabilizing microtubules.
The team genetically engineered mice by introducing a human gene into the animals to mimic the traits of Alzheimer’s disease in humans. This mutant form of tau caused memory impairment in the mice.
Researchers then treated the mice with epothilone D and found an increase in number of microtubules in the brain, with no evidence of toxicity. While this “preventative” approach proved successful, researchers are now looking toward a new study that is currently underway. This step will take an interventional approach by treating animals that already have the disease to see if effects can be reversed.
“No matter how many mouse studies you do, you don’t know if this drug is going to work in humans until you test it in humans,” Trojanowski noted. “The most important thing is that our discoveries lead to therapeutic interventions.”
Although Penn is not directly involved in the production of Alzheimer’s-targeting drugs, researchers hope the findings of the epothilone D animal model will prompt a clinical response to the increasingly prevalent disease.
