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The Besieged Brain

An immune response in the brain may contribute to Alzheimer's.

By Sarah Richardson
Sep 1, 1996 5:00 AMNov 12, 2019 4:29 AM


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Alzheimer’s disease, which afflicts some 4 million Americans, remains poorly understood--no one yet knows precisely what causes the disease, let alone how to cure it. But a number of researchers are beginning to support a surprising hypothesis about Alzheimer’s progression, namely that the brain’s own immune system may actually worsen the course of the disease.

One of the hallmarks of Alzheimer’s is brain lesions consisting in part of clumps of protein called beta-amyloid. This protein is a breakdown product of another protein--amyloid precursor protein, a structural component of neurons and other cells that is constantly being made in normal brains. And normally beta-amyloid is constantly eliminated. For reasons no one can yet pinpoint, but very likely relating to faulty genes, some people cannot eliminate the protein. In their brains, bits of beta-amyloid accumulate outside the neurons, ultimately forming insoluble sheets of the protein.

Although these sheets, or plaques, are associated with Alzheimer’s, it has never been clear if they are a cause or an effect of the disease. What is clear is that for some reason neurons around these lesions die, causing progressive dementia. Several years ago some neuroscientists began to suspect that immune cells in the brain, in their efforts to destroy the plaques, might release poisons and inadvertently harm neighboring, healthy brain cells. Similar misguided attacks by the immune system elsewhere in the body are known to occur in diseases such as lupus and rheumatoid arthritis.

Until about ten years ago, such a hypothesis would have been dismissed out of hand because immune cells weren’t known to exist in the brain. Traditionally, the brain had been viewed as immunologically privileged. Capillaries in the brain have specialized cell walls that prevent immune cells and molecules from entering and provoking a harmful immune response. An additional layer of cells called astrocytes surrounds the capillaries, reinforcing the barrier. When immune cells do somehow trespass into the brain and attack normal brain proteins, for example, the result can be the progressive paralysis of multiple sclerosis.

Over the past decade, however, researchers have slowly begun to realize that the brain has its own immune force--specialized cells called microglia. Much as scavenging macrophages patrol tissue in other parts of the body, eating up dead cells and pathogens, microglia patrol the brain, crawling over and around neurons. They help repair damaged neurons and may even play a role in brain development, migrating into the embryonic brain just in time, researchers suspect, to gobble up dying surplus neurons that have failed to make the right connections. Patrick McGeer, a neuroscientist at the Kinsmen Neurological Institute in Vancouver, British Columbia, became interested in the role of microglia in Alzheimer’s disease several years ago. He wondered whether the microglia were merely clearing away dying cells or actively attacking the plaques and perhaps damaging healthy cells in the process.

To find out, McGeer and other researchers conducted postmortem searches for complement proteins in the brains of Alzheimer’s victims. These proteins float in the bloodstream and bind to invaders, forming a coating that attracts--and activates--scavenging immune cells. The presence of complement proteins in the brain would be a sign that microglia were being activated to attack plaques. Until this recent research, though, nobody had thought complement proteins would be found in the brain, or at least not in a form that would do any damage.

One of the reasons for that belief was that complement proteins were considered too dangerous to exist near delicate brain tissue. Besides surrounding foreign bodies in the bloodstream, complement proteins can also bind to one another in a complement cascade, forming a structure that punctures an invader--and sometimes neighboring healthy cells as well. The punctured cells leak and die within four minutes. Complement proteins are like the pieces of an atomic bomb, says McGeer. You keep them separated because when you start getting them together you can cause a lot of damage.

Last year McGeer and several other researchers managed to isolate complement proteins in the brains of deceased Alzheimer’s patients. Moreover, McGeer found that the complement proteins bind both to the beta- amyloid plaques and to microglia cells.

McGeer believes this evidence implicates the brain in its own destruction. His theory of the progression of Alzheimer’s disease is that once the plaques form, complement proteins attach to them, attracting microglia to the site. Even if the complement proteins don’t puncture any healthy cells, the microglia--They’re little bags of poisons, says McGeer--release toxins in an attempt to destroy the plaques. But the microglia cannot kill or digest the insoluble amyloid, so the immune response never stops. More microglia are recruited, and more neurons die, says McGeer, by friendly fire.

The idea that the immune system may do more harm than the pathogen it attacks is not new. In tuberculosis, for example, lungs are damaged not by the bacterium but by the immune response to the bacterium. But researchers have never fully examined whether such immune responses play a role in Alzheimer’s, says McGeer.

McGeer’s theory opens up the possibility of a new avenue of treatment for Alzheimer’s patients. Anti-inflammatory drugs could suppress the microglia attacks and prevent the death of healthy brain tissue. McGeer estimates that treating Alzheimer’s patients with anti-inflammatory drugs-- and thus slowing the onset of the disease--could save the United States $40 billion annually in health-care costs.

A spate of provocative studies support McGeer’s hypothesis. He and his colleagues have found in a small study that a six-month course of an anti-inflammatory drug, indomethacin, arrested the cognitive decline of 28 patients. Another study looked at the medical records of 50 pairs of elderly twins and found that the twin who had taken anti-inflammatory drugs ran less risk of Alzheimer’s than the twin who had not. And just last March, a 15-year study of nearly 2,000 elderly people enrolled in the Baltimore Longitudinal Study of Aging found a 30 to 60 percent reduced risk of Alzheimer’s among those who had been taking anti-inflammatory drugs.

Despite these promising studies, Claudia Kawas, a neurologist at Johns Hopkins Medical School and an author of the Baltimore epidemiological study, cautions that inflammation may be but one player in the complex story of Alzheimer’s. What we are beginning to realize, she says, is that Alzheimer’s doesn’t strike later in life; it is probably the result of a host of insidious, lifelong assaults on the brain--inflammation among them. Still, Kawas is optimistic. Studies have shown that certain supplements--estrogen, for example--can lessen one’s risk of Alzheimer’s, and anti-inflammatory drugs may become one of a host of weapons to combat the disease. Alzheimer’s is a chronic degenerative disease, Kawas explains. I don’t think people realize that we are going to be able to treat this disease--much as high blood pressure is treatable. And it’s going to happen in my lifetime.

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