Waste: Is that the key reason for Alzheimer's

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Washington Post
Amy Marcus

Biological waste material normally is broken down by the part of the cell known as the lysosome. If something goes wrong in the process, toxins, made up largely of various proteins, start to build up and cause cells to deteriorate and die. When this happens in the brain, the accumulation of cellular waste products includes amyloid beta-protein, which has been linked with Alzheimer's and other types of dementia.

Researchers suggest that problems in the lysosome represent an early event in the dementia process that, if treated or reversed, could stop the disease from taking hold.

Ralph A. Nixon, professor of psychiatry and cell biology at New York University's Langone Medical Center and the Nathan Kline Institute, says experiments with mice with Alzheimer's disease have helped to support this theory. Dr. Nixon says he and his colleagues were able to prevent cognitive decline in the animals by improving the functioning of the enzymes in the lysosome so that the waste proteins were degraded and processed faster. Ideally, Dr. Nixon says, drugs would repair the defective mechanism intended to eliminate toxic proteins before damage is done to the brain.

Traditional drug development in Alzheimer's disease is taking too narrow an approach by focusing intensively on the buildup of amyloid beta-protein in the brain, Dr. Nixon says. That's because amyloid, although important, is just one of the many toxic proteins that swell the neurons when the lysosomal system breaks down. "The sheer bulk of waste proteins that are accumulating within the neurons in Alzheimer's disease brains is enormous,'' Dr. Nixon says.

Dozens of rare genetic conditions affecting children lead to the buildup of cellular toxins, which without treatment can cause neurological problems and sometimes death. Among the best known of these are Tay-Sachs disease and Gaucher disease. Moreover, a better understanding of how the lysosome functions could lead to treatments for other maladies, such as Huntington's disease and Niemann-Pick Type C.

Researchers are trying different approaches to target the lysosome as a possible treatment for Alzheimer's and other diseases. In some cases, they are trying to increase the activities of certain enzymes in the lysosome that help degrade the waste products. In other instances, they are trying to get the lysosomal system to work faster or more efficiently at recycling the waste products before they have a chance to build up and cause problems in the cell.

David C. Rubinsztein and a team of researchers at the Cambridge Institute for Medical Research in Cambridge, England, are taking a similar approach to target Huntington's disease, a fatal hereditary disorder that leads to a loss of neurons in the brain. Dr. Rubinsztein, a professor of molecular neurogenetics, says that one way to slow down or delay the onset of Huntington's disease may be to enhance the removal of the mutant huntington protein that is toxic to the cells.

Researchers screened a group of compounds already in use for various conditions and found that two hypertension drugs, clonidine and rilmenidine, speed up the removal of the mutant huntington protein from mice. In a study testing rilmenidine published earlier this year in the journal Human Molecular Genetics, mice with Huntington's disease were given the drug starting at five weeks and then tested from 12 weeks of age. The mice that got the drug did better than the mice that didn't get the drug, showing improvements in limb strength and tremors.

Early next year, a safety trial involving people who have early symptoms of Huntington's disease will be launched. Ultimately, if the drug appears to have an effect, Dr. Rubinsztein says they would like to give it to people before symptoms appear in the hopes that it could delay onset of the disease.

At the Mount Sinai School of Medicine in New York, researchers led by Yiannis A. Ioannou have been studying cyclodextrin, a compound that has extended the lives of mice with a lysosomal storage disorder called Niemann-Pick Type C (NPC). Although the exact mechanism for this effect isn't fully understood, Dr. Ioannou argues that the substance may work by stimulating the lysosomes in the mice neurons to dump out all of the stored waste products at once. This could be helpful for other neurodegenerative disorders that also have lysosomal involvement, he says.

Cyclodextrin is already being tested in mice with Alzheimer's disease by researchers including Dr. Nixon and is being given on an experimental, individual basis to a small number of children in the U.S. and Brazil who have NPC disease. Still, one reason why doctors haven't yet set up a clinical trial in NPC patients is because they aren't sure how the drug is working, since cyclodextrin is believed not to be able to cross the blood-brain barrier that separates circulating blood from neuronal cells.

In a paper published earlier this month in Plos One, Dr. Ioannou and his colleagues demonstrated that cyclodextrin pokes holes in cell membranes, triggering lysosomes to empty their contents in an effort to repair the damage. Now the Ioannou lab is studying whether this signal can also be transmitted across the blood-brain barrier to the lysosomes in brain cells to tell them to empty their stored waste products. Understanding how this works may make it easier to develop drugs that may help not only patients with NPC disease but a number of other neurodegenerative disorders, Dr. Ioannou says.