November 03, 2004
Injected Antibodies May Halt Alzheimer's Plaque Growth

Injected antibodies might avoid the side effects produced by vaccination against Alzheimer's amyloid plaques.

Researchers at the University of Illinois at Chicago have had preliminary success with a method of immunization intended to dissolve the plaques in brain tissue that are associated with Alzheimer's disease.

When injected directly into the brain of mice, antibodies against a plaque protein retarded growth of the plaques by up to two months. No adverse side effects were found.

"By injecting the antibodies directly into the brain, we were able to circumvent the problems others have encountered in developing a vaccine for this terrible disease," said Neelima Chauhan, research assistant professor in the UIC College of Medicine.

Results of the study appear in the current issue of the Journal of Neuroscience Research.

Two methods of immunization have been tried in Alzheimer's disease. In the first, called active immunization, researchers inject the antigen itself -- pieces of the sticky beta amyloid protein that constitutes the plaques -- into patients to spur the production of antibodies that should neutralize the protein and prevent it from accumulating in brain cells.

But after success in animals, clinical trials of active immunization failed when 6 to 8 percent of the patients in the study developed meningocephalitis, an inflammation of the tissue surrounding the brain.

Passive immunization did not even succeed in animal studies. In this method, researchers inject ready-made antibodies, rather than the antigen, into the animal. But high concentrations of the antibodies are required to be effective, and the large doses were found to cause hemorrhaging and inflammation.

Aware of such problems, Chauhan tried a modified passive immunization method in laboratory mice that are used as a model for the disease. In a single injection, she delivered the antibody directly into the third ventricle, a narrow cavity located between the two hemispheres of the brain, and then examined the animals' brain tissue at one, four and eight weeks.

Since the antibody did not have to circulate throughout the mouse's body where it might be absorbed, Chauhan was able to use a smaller dose than in other passive immunization studies.

Note the plaques came back more slowly in young mice. The ability to clear the plaques by itself would not fully restore brains to a more youthful condition in which plaques would not form in the first place. We still need many other rejuvenation therapies for the brain.

At one and four weeks, the density of amyloid protein was 67 percent less than in control animals. But by eight weeks, with no further antibody injections, the protein had again accumulated. The younger the animals were, the slower the plaques regrew.

No side effects, such as hemorrhaging or inflammation, were evident.

"The results suggest that periodic administration of antibodies directly into the brain might offer a safer method for treating Alzheimer's," Chauhan said. "The vaccine reduces the accumulation of amyloid proteins for at least four weeks, providing a window during which other treatments could be used to prevent the formation of new plaques."

Alzheimer's is an age-associated degenerative neurological disease and the leading cause of dementia in older people. An estimated 10 percent of Americans over the age of 65 and half of those over age 85 have Alzheimer's.

Imagine the cost of Alzheimer's ballooning up to $300 billion per year or more in the United States in a few decades. Makes the cost of research to cure it seem very cheap by comparison. Keep in mind that the money spent finding a way to prevent Alzheimer's is a fixed cost. Once the cure is found the research on that topic doesn't have to continue. Whereas if we do not get a cure for decades to come them the high yearly cost of treatment keeps rising and it goes on continually. Biomedical research spending can produce cures that basically pay from the day the cure is found until humans no longer exist in this universe (I'm assuming that we won't be able to transfer our knowledge to humans who may exist in parallel universes but that assumption may some day prove to be incorrect).

Currently, more than 4 million Americans suffer from the disease and the number is projected to balloon to 10 to 15 million over the next several decades. Alzheimer's is now the third most expensive disease to treat in the United States, costing close to $100 billion annually.

You can read the abstract of the paper here: Effect of age on the duration and extent of amyloid plaque reduction and microglial activation after injection of anti-A[Beta] antibody into the third ventricle of TgCRND8 mice.

While the Elan Pharmaceuticals experimental vaccine AN-1792 against Alzheimer's amyloid plaques caused brain inflammmation in a small subset of people treated I still think a better vaccine may be able to eventually work well against amyloid plaques. In fact, a new oral vaccine has just been tested in mice and shows promise.

Alzheimer's disease is characterized by progressive loss of cognitive function due to amyloid-beta (Aß) deposits in the central nervous system. If these deposits could be stopped or slowed, Alzheimer's disease might become more manageable. In the current issue of the Journal of Alzheimer's Disease, a novel paper from researchers from the National Institute for Longevity Sciences, NCGG, Japan and Center for Neurological Diseases, Brigham & Women's Hospital, Harvard Institute of Medicine shows that a new oral vaccine treatment is effective in reducing Alzheimer's disease pathology.

Immunization results from the production of antibodies which attack the harmful agent, using the body's own defenses to remove the threat. In an earlier immunization study, 6 percent of the subjects developed acute meningoencephalitis, most likely caused by autoimmune T-cell activation. This caused the trial to be stopped. By developing vaccines that can minimize this T-cell activation while retaining the production of Aß-antibodies, a safer treatment might result.

The researchers attached Aß DNA to an adeno-associated virus vector and administered this vaccine to mice orally. Not only were the Aß levels decreased, but the T-cell immune response was significantly reduced. A single dose of this vaccine enhanced the production of Aß-antibodies for more than 6 months. Immunohistochemistry of the mouse brain tissue showed that the extra-cellular amyloid deposits were clearly decreased compared to the non-treated mouse.

Hideo Hara, M.D, writes "This new oral vaccine does not induce strong T cell immune reactions, and hence it could reduce the side effect of such meningoencephalitis…This new therapy seems to be effective for prevention and treatment of Alzheimer's disease."

The article is "Development of a safe oral Aß vaccine using recombinant adeno-associated virus vector for Alzheimer's disease" by Hideo Hara, Alon Monsonego, Katsutoshi Yuasa, Kayo Adachi, Xiao Xiao, Shin'ichi Takeda, Keikichi Takahashi, Howard L. Weiner and Takeshi Tabira. It appears in the Journal of Alzheimer's Disease, Vol.6, Number 5, published by IOS Press

You can view the abstract here.

Share |      Randall Parker, 2004 November 03 03:35 PM  Brain Alzheimers Disease

Garson Poole said at November 3, 2004 11:46 PM:

Randall Parker,
Thanks for the update on Alzheimer's research advances. I had been reading about the vaccine research for years and was disappointed when the Elan experimental trial was suspended. It would be great if the "amyloid plaques" hypothesis is correct and some vaccine-type treatment works.

There is a journalist at the "The Wall Street Journal" named Sharon Begley who has been writing about alternatives to the "amyloid plaques" hypothesis. Below is an excerpt from one of her articles:

Beliefs about what causes this merciless disease (Alzheimer's) have taken on such a religious fervor that one group is called tauists, after a protein called tau that forms "neurofibrillary tangles" inside the neurons and, say these scientists, kills neurons responsible for memory and thought. Another is called baptists, after the beta-amyloid protein that forms plaques around brain neurons and, say its accusers, causes neuron-killing tau tangles or kills neurons directly, or both. Apostates think amyloid plaques sop up neurotoxic proteins along with poisonous metals such as zinc and copper, and that eliminating plaques could therefore harm patients.

Here are links to three of her articles:

Is Alzheimer's field blocking R&D into other causes? [April 9 2004]

Scientists fight a narrow view of Alzheimer's cause [April 16 2004]

Debate over Alzheimer's origins causes divisions [August 6 2004]

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