Psychiatric drug may thwart Alzheimer's

By LIDIA WASOWICZ, UPI Senior Science Writer   |   May 21, 2003 at 1:43 PM   |   0 comments

A drug used for 50 years to treat manic depression could provide a one-of-a-kind, two-punch defense against Alzheimer's disease, a dementia-fomenting disorder that affects 18 million people worldwide, scientists said Wednesday.

Tested in mice with a form of the neurodegenerative disease characterized by progressive senility, the drug lithium delivered crippling blows to two notable hallmarks of the ailment that ravages the brain.

Researchers discovered the compound took aim at both the cell-strangling buildup of an abnormal protein called amyloid plaque and the communications-stifling jumble of malformed nerve cells called neurofibrillator tangles.

The study has a two-fold significance, investigators told United Press International. Tried and true lithium provides a known quantity in its effects on the body and a fast track to marketing approval, bypassing the cost and time lag required to develop and test new compounds and gain Food and Drug Administration approval. Also, unlike anything else on the market or drawing boards, the drug's double-whammy promises to provide an additional boost to the anti-Alzheimer's arsenal.

"The identification of a widely prescribed, relatively safe drug with the potential to slow or prevent the onset of AD is significant," said lead study author Dr. Peter Klein of the Department of Medicine and Division of Hematology at the University of Pennsylvania School of Medicine in Philadelphia.

The new insights should lead to additional therapeutic targets, researchers said.

"This is certainly an exciting advance," said James Woodgett of Canada's Ontario Cancer Institute in Toronto, who analyzed the findings in an accompanying commentary.

"For drug companies, it gives them an immediate new target," he told UPI. "For the lay public, it provides hope that new, more effective treatments are in the pipeline. If lithium is found to be effective, that pipeline might be unusually short. If not, it will likely take another 5 to 10 years to translate into a drug."

The researchers issued a pair of caveats: they do not yet know whether they can successfully duplicate the animal results in humans and the elderly do not tolerate lithium well, succumbing to kidney disorder and other serious side effects.

"These tend to be more frequent in older patients," Klein said. "The side effects of lithium are generally reversible upon discontinuation of the drug."

The UPenn quartet of Klein, Virginia Lee, co-director of the Center for Neurodegenerative Disease Research and professor of pathology and laboratory medicine, and researchers Christopher Phiel and Christiana Wilson found lithium can put the brakes on plaques forming in the brains of mice with a form of Alzheimer's. It does so by interfering with an enzyme called glycogen synthase kinase-3.

The deranging and deadly deposits of excess amyloid protein in the brain suffocate nerve cells by blocking transport of crucial blood supplies. The tangles of malformed cells and mounds of menacing protein also stifle neurons' ability to communicate, causing them to die.

"Our current study, combined with earlier work, shows that the two processes associated with the progression of Alzheimer's disease -- the build-up of protein deposits known as amyloid plaques and neurofibrillary tangles -- can be inhibited with lithium," said Klein, who also is an investigator at the Howard Hughes Medical Institute in Chevy Chase, Md.

"Our findings have interesting implications for the potential use of lithium in preventing or disrupting the growth of these plaques and tangles in patients, since lithium is known to be relatively safe in humans when administered properly."

No other drugs have shown this dual effect, scientists said.

"While a couple of years ago understanding basic mechanisms was the main issue, we have moved now towards identification of potential drug targets, and the current study adds yet another one," Dr. Bart De Strooper of the Center for Human Genetics in Leuven, Belgium, who analyzed the results, told UPI.

The findings, which will be published in the May 22 issue of the British journal Nature, build on previous work by Klein and Lee, who analyzed the causes of the gradual loss of brain cells typical of Alzheimer's that over the course of 3-to-20 years leads to dementia, disability and death.

"The effect it has on an otherwise healthy person, as well as the caregiver, is tragic," Woodgett, whose father is in the late stages of the disease, said.

The mind-wasting disorder progressively robs its victims of their mental faculties, eventually leaving them wheelchair-bound and in need of constant care. The rate of the disorder, which sets in at an average age of 79, is expected to nearly double to 34 million by 2025 as the world's population continues to grow older.

"Lithium is not an ideal drug, but this study will likely stimulate clinical trials or at least epidemiological studies to assess correlations between lithium treatment and onset of Alzheimer's disease," Woodgett said.

"I believe we'll be able to initially control and then prevent Alzheimer's disease within the next generation," he said. "While we will surely die of something else, it is unlikely to be such a horrible and devastatingly premature way to die as is endured by the sufferers of Alzheimer's disease."

© 2003 United Press International, Inc. All Rights Reserved. Any reproduction, republication, redistribution and/or modification of any UPI content is expressly prohibited without UPI's prior written consent.
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