Disease Mechanism In Hereditary Dementia Discovered -- Treatment Implications Seen For Alzheimer's And Other Neurodegenerative Diseases

A report on the study appears in the December 4 issue of Science.

The research team investigated a dementia linked to more than 10 different genetic flaws on chromosome 17 known as frontotemporal dementia and parkinsonism (FTDP-17). They found that, in FTDP-17, mutant versions of a protein called tau are unable to fulfill one of the protein's crucial roles, which is to stabilize structural elements in neurons called microtubules. In addition to shoring up the scaffolding of a cell, microtubules also form the basis of an intracellular transport system -- especially important in neurons, which have extensions called axons that can reach a full meter through the body. With microtubule assembly disrupted, these cells can die.

"The bottom line here is that there is loss of tau function with these mutations, and the function of tau is to stabilize microtubules," says Virginia M.-Y. Lee, PhD, a professor of pathology and laboratory medicine and senior author on the study. "In neurons, with their long, delicate axons, microtubules are extremely important not only as structural entities but also as a kind of railroad along which the cells move various materials critical to their survival."

The tau protein is also the main component of the abnormal tangles in neurons that, along with amyloid plaques, define Alzheimer's disease. Tau tangles are seen in other dementing diseases, too, such as Pick's disease. Prior to this study, however, scientists had been unable to directly associate tau with a disease-causing mechanism, although they have long suspected that the tangles interfere with cellular processes in some way.

Also, they knew that laboratory mice engineered to develop amyloid plaques to the exclusion of the tangles do not lose neurons nor do they develop disease. In contrast, the tau tangles are signature features in FTDP-17 while the amyloid plaques are not present, yet neuronal death and disease result, pointing to a primary role for the tangles over the plaques.

Still, perhaps because several genetic flaws affecting production of the amyloid protein had been identified in inherited forms of Alzheimer's disease, many neuroscientists have focused their attentions on the plaques. Recent discoveries of genetic errors in hereditary FTDP-17, however, opened the door for the current study, and the results re-emphasize that the disease-causing capability of mutant tau must not be underestimated.

"There's no doubt that tau tangles alone can lead to disease, while you cannot say that for the amyloid plaques," says John Q. Trojanowski, MD, PhD, a professor of pathology and laboratory medicine and coauthor on the study. "These results suggest that sporadically formed tau tangles, similar to those found in hereditary FTDP-17, may be causal features in many neurodegenerative diseases, including Alzheimer's disease."

The findings indicate useful strategies to pursue in pharmaceutical development. Drugs that mimic the properties of normal tau, for example, might be able to stabilize microtubules to slow or stop disease progression. Taxol, better known as an anti-cancer agent, works by stabilizing microtubules to interfere with the rapid cell division seen in cancer. The same action might preserve microtubules in neurodegenerative diseases in which tau pathologies are at work. Taxol, however, is not able to cross the blood-brain barrier to reach diseased neurons, but related compounds might be developed that could reach neuronal targets.

Leaders in the scientific community suggest the new study could lead to further insights.

"These exciting findings provide an important link to understanding how mutations in the tau gene may affect cell function in FTDP-17," says Creighton H. Phelps, PhD, director of the Alzheimer's Disease Research Centers Program at the National Institute on Aging. "The abnormal protein disrupts normal brain cell function, probably leading to cell death. Similar changes occur in other brain diseases, such as Alzheimer's and Pick's disease, and further studies are needed to deduce the common pathological mechanisms involved."

The lead author on the study is Ming Hong, MD. Penn-based coauthors on the study, in addition to Lee and Trojanowski, include Victoria Zhukareva, PhD; Vanessa Vogelsberg-Ragaglia, PhD; and Lee Reed, MD. Additional coauthors are affiliated with the Mayo Clinic Jacksonville (FL); the University of California, Los Angeles; the University of Washington, Seattle; the University of California, San Francisco; and Washington University, St. Louis. Funding for the work was provided by the National Institutes of Health.

The University of Pennsylvania Medical Center's sponsored research and training ranks third in the United States based on grant support from the National Institutes of Health, the primary funder of biomedical research and training in the nation -- $175 million in federal fiscal year 1997. In addition, for the third consecutive year, the institution posted the highest annual growth in these areas -- 17.6 percent -- of the top ten U.S. academic medical centers.