June 10, 2010 / 4:32 PM / 8 years ago

Faulty gene leads to protein buildup in Alzheimer's

CHICAGO (Reuters) - A brain mechanism that acts like a recycling plant for toxic proteins goes haywire in people with a gene mutation linked with Alzheimer’s disease, U.S. researchers said on Thursday, unveiling a discovery offering a new lead for drug companies.

They said the gene presenilin 1, which is linked to the early development of Alzheimer‘s, plays a role in digesting toxic proteins.

In people with Alzheimer‘s-related mutations, this process is faulty. Fixing it could help prevent the buildup of toxins in the brain before they do damage.

“This is cellular garbage. If the recycling factory is broken or shut down, the garbage will accumulate on the streets,” said Dr. Ralph Nixon, an Alzheimer’s researcher at New York University’s Langone Medical Center, whose study appears in the journal Cell.

“In this case, it will accumulate in cells and eventually kill the cells,” Nixon said in a telephone interview.

This new understanding of the role of a gene so closely linked with Alzheimer’s disease suggests a fresh approach to drug development.

So far, researchers have focused on cleaning up the protein mess that accumulates when this brain mechanism goes awry.

These clumps made up of beta amyloid protein are considered a hallmark of Alzheimer’s disease, but drugs that remove these proteins so far have not succeeded in arresting the steady decline of thinking and memory that accompanies the disease.

“We have been ignoring other pathways that may be essential to treating Alzheimer’s disease. We’ve been basically tracking one way to approach therapy, which is to eliminate amyloid protein from the brain,” Nixon said.

For the study, Nixon’s team did experiments in mice genetically engineered to develop Alzheimer’s disease and in skin cells of people with Alzheimer’s caused by mutations in the presenilin gene, which activates lysosome enzymes that digest waste proteins during a process called autophagy.

In both cases, they found the mechanism for clearing away damaged proteins was severely impaired.

“If you inhibit this clearance mechanism with drugs that block the digestive enzymes, you can produce similar types of manifestations,” Nixon said.

Genetically manipulating the system so enzymes work more efficiently can improve Alzheimer’s symptoms in mice, he said.


Early onset Alzheimer’s disease, which strikes between age 30 and 60, is rare. But Nixon said there are likely other genes or pathways related to the more common form of Alzheimer’s disease that cause the same system to malfunction.

“This study expands our understanding of the role presenilin 1 mutations may play in Alzheimer’s pathology,” Dr. Richard Hodes, director of National Institute on Aging, part of the National Institutes of Health, said in a statement.

“While more research is needed, lysosome disruption may be worth exploring as a potential target for new therapeutics to treat, prevent or delay this progressive and debilitating disease.”

Nixon said several drug companies have expressed interest in the findings, but he would not name them.

Current drugs help manage symptoms but, so far, no treatment can stop the progression of Alzheimer‘s, which can start with vague memory loss and confusion before progressing to complete disability and death.

The government, private insurance and individuals spend $172 billion a year to care for people with Alzheimer’s disease, the most common cause of dementia that affects 26 million people globally.

The Alzheimer’s Association estimates that from 2010 to 2050, the annual cost of caring for Americans 65 and older with Alzheimer’s will increase more than sixfold to $1.08 trillion.

Editing by Alan Elsner

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