X-Message-Number: 15774
From: "Mark Plus" <>

Subject: "Once Thought Permanent, Alzheimer's Plaques Are Cleared From The 
Brains Of Liv"
Date: Thu, 01 Mar 2001 08:26:21 -0800



Source:   Massachusetts General Hospital (http://www.massgeneral.org)

Date:   Posted 3/1/2001

Once Thought Permanent, Alzheimer's Plaques Are Cleared From The Brains Of 
Living Mice

BOSTON   February 28, 2001   Lab mice bred to develop the notorious plaques 
of Alzheimer's disease had a majority of their plaques disappear 3 to 8 days 
after treatment with anti-plaque antibodies. Massachusetts General Hospital 
(MGH) researchers, working with scientists at Elan Pharmaceuticals, cleared 
70 percent of plaques by applying the antibodies directly to the mouse 
brains through tiny holes in their skulls. Their findings appear in the 
March Nature Medicine.
A year and a half ago, Elan scientists showed that they could prevent plaque 
formation in the Alzheimer's-prone mice by vaccinating them with a protein 
found in the plaques, called amyloid-beta. But this is the first time that 
anyone has been able to clear pre-existing plaques in a living animal points 
out Bradley Hyman, MD, PhD, an MGH neurologist and senior author of the 

"No one has ever directly demonstrated the clearance of amyloid-beta 
deposits," says Brian Bacskai, PhD, an assistant in neurology at MGH and 
lead author of the study. "This was an especially surprising process because 
it was so rapid. It really took only a few days for what looks to be almost 
complete clearance of amyloid-beta deposits."

The experiments signify another achievement: This is the first time that 
anyone has observed plaques in a living animal. Too minute to be imaged by 
conventional non-invasive methods such as magnetic resonance imaging (MRI) 
and computed tomography (CT), plaques have only been observed by microscopic 
examination of post mortem brain samples. The MGH team made their 
observations on the living animals using a newly invented device, a 
multi-photon microscope.

"With our ability to image the plaques, we could clearly determine what 
happens to plaques before and after treatment with anti-amyloid-beta 
antibodies," says Bacskai.

Although it is still too early to know whether or not this result will one 
day apply to treatment in patients, the MGH scientists see it as an 
important pair of proof-of-principles. First, Alzheimer's plaques can be 
reversed. Second, the plaques can be reversed by the external application of 
antibodies rather than by internally mustering up the immune army of T cells 
and B cells, as is done through a vaccination.

It was a suspicion that plaques were degraded naturally in the brain, even 
in people unaffected by Alzheimer's, that inspired the team to undertake 
their experiment in the first place. "We thought that plaques would be 
deposited and resorbed as a natural life event," Hyman says.

To explore the hypothesis, the researchers turned to the recently developed 
multi-photon microscope, which can image deeper and more precisely inside 
tissue than conventional microscopes. The multi-photon microscope works by 
training an intense beam of near infrared light on fluorescent tracers 
inside tissue.

In preparation for their experiment the MGH researchers gave 
Alzheimer's-like mice bred by Elan pharmaceuticals a trio of fluorescent 
agents. (The mice carry a gene for a mutant form of APP, a precursor of the 
amyloid protein that makes up plaques.)

They applied the first of the fluorescent tracers   thioflavine s, a 
well-known marker of plaques   directly to the brains of mice through holes 
in their skulls. Next, they applied plaque-fighting amyloid-beta antibodies 
  also labeled with a fluorescent tag   to the same regions. Both 
fluorescent substances bound to the plaques. Finally, they injected a 
fluorescent tracer into the capillaries in the vicinity of the plaques, 
which provided a blood vessel map of the plaque's location.

Using this road map, they returned to the same locations 3 to 8 days later 
and stained once again for the plaques. In control animals they were able to 
relocate 80 percent of the plaques that they had seen the first time; after 
application of the antibody, seventy percent of the plaques had disappeared.

Microglia agents of the immune system surrounded the plaques that were not 
yet cleared. If the anti-amyloid-beta antibodies are working through these 
microglia middlemen, there may be other ways to prod the microglia to carry 
out their plaque-fighting mission.

It is not yet clear what will happen to neurons near the vanished plaques 
but the researchers plan to find out. "Once we can see where a plaque is, we 
can also ask whether neurons in their area are healthy or not; the real key 
is to understand how to improve the function of the brain." says Hyman.

Funding for this study was provided by the National Institute of Aging, an 
Alzheimer Association Pioneer Award and the Walters Family Foundation.

The Massachusetts General Hospital, established in 1811, is the original and 
largest teaching hospital of Harvard Medical School. The MGH conducts the 
largest hospital-based research program in the United States, with an annual 
research budget of more than $200 million and major research centers in 
AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, 
transplantation biology and photo-medicine. In 1994, the MGH joined with 
Brigham and Women s Hospital to form Partners HealthCare System, an 
integrated health care delivery system comprising the two academic medical 
centers, specialty and community hospitals, a network of physician groups 
and nonacute and home health services.

Editor's Note: The original news release can be found at 


Note: This story has been adapted from a news release issued by 
Massachusetts General Hospital for journalists and other members of the 
public. If you wish to quote from any part of this story, please credit 
Massachusetts General Hospital as the original source. You may also wish to 
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