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Ever since the German doctor Alois Alzheimer gave his name to the dementia suffered by many of the aging, nearly a century ago, it has been known that the brains of these patients show an accumulation of plaques. Now, scientists at Weill Cornell Medical College have produced important new evidence that the beta-amyloid peptide in these plaques may originate within the nerve cells, not outside, and that the observed extracellular plaques may actually be like "tombstones," or remnants, of the destructive intracellular beta-amyloid.

This evidence, which is set out in an article in this month's American Journal of Pathology, suggests that doctors possibly need to be careful about the current predominant strategy of trying to reduce the extracellular accumulation of plaques. That is the judgment of Dr. Gunnar K. Gouras, the senior author of the article, who is Assistant Professor of Neurology and Neuroscience at Weill Cornell Medical College and Assistant Attending Neurologist at NewYork-Presbyterian Hospital-Weill Cornell Medical Center.

The suspicion that the beta-amyloid plaques of Alzheimer's disease originates intraneuronally rather than extraneuronally has been growing in recent years, Dr. Gouras says, but it is still somewhat controversial. In the new article, he and his colleagues report the results of some powerful observations made with electron microscopy. They investigated human brains as well as a mouse model of Alzheimer's disease.

"Dr. Alzheimer and others discovered that people who died with dementia had abnormal deposition in their brains of plaques and tangles," Dr. Gouras says. "The tangles clearly occurred within nerve cells and were also found in a variety of other brain disorders, but the origin of the plaques in the extracellular space was a mystery. Infectious agents were suspected, but in time, the conventional view became that the plaques resulted from the gradual extracellular accumulation of beta-amyloid, which, 18 years ago, was found to be their major peptide constituent."

Dr. Gouras continues, "In collaboration with Dr. Teresa Milner, Professor of Neuroscience at Weill Cornell, we found by electron microscopy that the beta-amyloid actually accumulates within nerve-cell synaptic compartments, at the connections with other cells, and that the beta-amyloid destroys these synapses from within. The plaques are like the tombstones of the synapses that are left when the synapses are overwhelmed and broken down by beta-amyloid."

Specifically, the authors looked at beta-amyloid 42, a long form of the peptide that has been shown to be important in Alzheimer's disease. They made visible the locations of this peptide by using a monoclonal antibody for beta-amyloid 42. These locations proved to be the outer membranes of multivesicular bodies (MVBs) in the nerve cells. "Our most critical control," Dr. Gouras says, "is that this type of MVB with beta-amyloid is not present in amyloid-precursor-protein knockout mice"—that is, mice missing the gene for that peptide.

"Our work implies that we should be careful about using plaque reduction as the sole measure for effective therapy," Dr. Gouras says, "since the actual damage begins within the nerve cells. The critical aim for therapy may be to decrease beta-amyloid within nerve cells."

In a special online discussion, Dr. Gouras poses some further questions for consideration and investigation about beta-amyloid 42 in multivesicular bodies (MVB A-beta42), including:

• What is the source of MVB A-beta42? Is some, all, or any of it derived from extracellular A-beta42 or synaptically released A-beta42?
• Is there a normal function of MVB-associated A-beta42?
• What is the mechanism by which MVB A-beta42 increases with aging?

These questions and others will be taken up in the Alzheimer Research Forum (www.alzforum.org) on Tuesday, November 26.

Collaborating authors of the article are Reisuke H. Takahashi, Teresa A. Milner, Feng Li, Ellen E. Nam, Mark A. Edgar, Haruyasu Yamaguchi, M. Flint Beal, Huaxi Xu, and Paul Greengard. Drs. Takahashi, Milner, Li, Nam, and Edgar are all at Weill Cornell Medical College, and Dr. Beal is Chairman of the Department of Neurology and Neuroscience at the Medical College. Dr. Yamaguchi is at Gunma University School of Health Sciences, Gunma, Japan. Dr Greengard, a Nobel Laureate, and Dr. Xu are at The Rockefeller University.

The research was supported by the National Institutes of Health, the Alzheimer's Association, the American Academy of Neurology Education and Research Foundation, and a Paul Beeson Physician Faculty Scholar Award (to Dr. Gouras).