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Immune Cells Protect Against Alzheimer’s Disease

For release: Wednesday, May 9, 2007

Immune cells in the brain help slow the accumulation of beta-amyloid that is a hallmark of Alzheimer’s disease (AD), a new study shows.  The researchers also found that a specific immune system protein strongly affects mortality in a mouse model of AD.

“This study shows that the immune system is protective in early Alzheimer’s disease,” says Andrew D. Luster, M.D., Ph.D., of Massachusetts General Hospital in Boston, who helped lead the new study.  The results suggest that increasing the activity of immune cells called microglia may help to prevent or treat early AD.  The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the April 2007 issue of Nature Medicine.[1]

The study helps to resolve a long-standing question about the role of microglia in the development of AD.  Previous research has shown that microglia accumulate near amyloid clumps (plaques) in the brains of people with AD, and that they can degrade beta-amyloid.  However, microglia also produce chemicals that may contribute to neuron loss and cognitive impairment.

Dr. Luster, along with Joseph El Khoury, M.D., of Massachusetts General Hospital, and others, developed mice that produce a mutant amyloid precursor protein (APP) and lack an immune receptor called Ccr2.  The mutant APP gene causes AD in humans.  Previous studies have shown that Ccr2 is expressed on the surface of microglia and helps them accumulate at sites of brain injury.

The APP mice without Ccr2 initially appeared healthy.  However, 85 percent of them died by 130 days of age, compared to 65 percent of mice with half the normal amount of Ccr2, 30 percent of mice with normal amounts of Ccr2, and 1 percent of control (wild-type) mice.  This showed that the amount of Ccr2 activity strongly influenced mortality.  The Ccr2-deficient mice also accumulated much more beta-amyloid in their brains by 65 days of age than the other mice.

The beta-amyloid deposits in the brains of the mice were located primarily in small blood vessels.  Postmortem examinations of several Ccr2-deficientmice showed areas of brain hemorrhage (bleeding), suggesting that the premature death in these mice was at least partly due to hemorrhage.  These findings are similar to those in mouse models for a disease called cerebral amyloid angiopathy (CAA), which causes beta-amyloid to accumulate in the brain's blood vessels.  CAA increases the risk of hemorrhagic stroke.

Additional studies showed that Ccr2 plays a major role in helping microglia migrate to beta-amyloid deposits and break them down.  Mice with Ccr2 had about six times more microglia in their brains than mice without Ccr2. Most of the microglia appeared to have come from the blood.

"This study suggests that the innate immune system senses something wrong and responds to it," says Dr. Luster.  "It shows that Ccr2 receptors are very important for getting microglia from the bone marrow, where they are produced, into the brain."

Previous studies of a vaccine that increases the immune response to beta-amyloid have shown that immune substances called antibodies can promote clearance of toxic accumulations of beta-amyloid.  However, this study is the first to directly show that the innate immune response also plays a role, and that it can modulate early disease progression in animals, Dr. El Khoury says. 

“Understanding the interaction of the immune system with the brain is critical for determining the mechanisms of many neurological diseases, as this significant work highlights," says Michael Nunn, Ph.D., the NINDS program director for this study.  "More studies of Ccr2, other related chemokines, and their receptors will unveil avenues toward the development of therapies in Alzheimer’s, Creutzfeldt-Jacob, Parkinson’s, ALS, AIDS, and other diseases.”

While the microglia appear to protect the brain in early AD, it is still unclear whether they are helpful or harmful in later stages of the disease, Dr. El Khoury notes.  The microglia may eventually become overwhelmed by beta-amyloid, and toxic byproducts of their activity may then contribute to the disease. 

The study suggests that gene therapy, drugs, or other therapies that increase the activity of Ccr2 might be useful for treating early AD and CAA, the researchers say.  However, much more research is needed before such therapies will be ready for testing.  Drs. Luster and El Khoury are now planning studies to determine if such an approach might work.  They also plan to study exactly how Ccr2 helps microglia migrate in the brain and to determine whether other chemokine receptors also play a role.  Researchers also need to determine whether Ccr2 function is abnormal in people with AD.

The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system.  The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services.  It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases.  For more information about NIH and its programs, visit

-By Natalie Frazin

[1] El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD.  “Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease.”  Nature Medicine, April 2007, Vol. 13, No. 4, pp. 432-438.

Last Modified May 9, 2007