Alzheimer's may not be an inflammation after all

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October 27, 2003

Brain Not Inflamed?

Alzheimer's may not be an inflammation after all

By Dennis Watkins

 

Researchers have for years observed that patients regularly taking ibuprofen,

naproxen or other nonsteroidal anti-inflammatory drugs seem to have less risk of

developing Alzheimer's disease. Some researchers hypothesize that the

Alzheimer's-diseased brain is actually inflamed and that damage happens when the

microglia, the brain's immune cells, become overactive and attack healthy

neurons. New research, however, indicates that the opposite may be

happening--that, as microglia age, they lose their ability to protect the brain.

Wolfgang J. Streit and his colleagues at the University of Florida compared

autopsy tissue from two nondemented brains, one of a 38-year-old man and the

other of a 68-year-old man. Many of the microglia in the older man's brain had

lost their fine branches or were otherwise deformed. Streit found even more of

these withered microglia in the brains of people who also had high levels of

beta-amyloid protein--a hallmark of Alzheimer's. Streit hypothesizes that

beta-amyloid may cause the deformities in microglia.

Moreover, Streit's lab examined in vitro cultures of rat microglia and

determined that over time, their telomeres shorten (as they do for most other

aging cells). Telomeres are end caps on chromosomes that help to maintain the

integrity of the genes; as they shorten, the cells lose the ability to replicate

and begin to die off. So " if we can keep our microglial cells healthy, then our

neurons will be in good shape, " Streit suggests. (Telomeres of neurons do not

shorten.)

In further defense of his theory that aging microglia are associated with

Alzheimer's, Streit points to a drug trial in the June 4 Journal of the American

Medical Association. Contrary to previous preliminary findings, the study showed

that Alzheimer's patients taking anti-inflammatory drugs fared no better than

those taking a placebo. " I'm discouraged by this class of drugs on the disease, "

admits Paul S. Aisen, a neurologist at Georgetown University and lead author of

the work. " Personally, I'm looking at other approaches to treatment that are not

related to inflammation. "

Aisen believes that microglia could potentially act both as protector and

attacker. " There is evidence for both viewpoints, even though they are

exclusive, " Aisen says. " I just don't think we have evidence of what the net

effect is of microglia during Alzheimer's. " The key to this puzzle, he explains,

lies in the interaction between microglia and beta-amyloid protein. In

Alzheimer's patients, the proteins form tangled plaques in the brain. Microglia

could be clearing away these harmful plaques.

Increasing the number of microglia, however, may have dangerous side effects. In

January 2002 trials of a drug called AN1792, which was designed to immunize

patients against the accumulation of beta-amyloid, were stopped because four

subjects developed encephalitis. One woman was so debilitated after treatment

stopped that doctors could not even give her a psychological examination, and

she died less than two years after beginning therapy. " Anybody who stimulates

inflammation is playing with physiological matches, " warns Patrick McGeer, a

neurologist at the University of British Columbia. McGeer adds that if

Alzheimer's resulted from the aging of microglia, then giving a patient

anti-inflammatory drugs to further suppress the immune response would exacerbate

the disease. Streit, on the other hand, argues that the microglia were not

functioning to begin with, so there was nothing to suppress.

John Breitner, an epidemiologist at the University of Washington, is studying

whether anti-inflammatory drugs can prevent the disease from developing in the

first place. Even if he discovers that the drugs are effective, Breitner says,

that will still not explain exactly how they work, leaving the door open to a

wide variety of theories on Alzheimer's and microglia. " We may all be barking up

the wrong tree, " he speculates. " It may be something that none of us has looked

at. "

 

Dennis Watkins is a science writer based in Woodbine, Md.

 

 

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