A Tiny Protein Called ADDL Could Be the Key to Alzheimer’s

By Tom Valeo

Scientists have long suspected that the protein clumps and tangles identified by Alois Alzheimer in 1907 somehow cause the disease that bears his name, probably by killing neurons. Now some researchers are blaming a much smaller form of protein, one that apparently produces memory deficits merely by binding to neurons and disrupting their ability to transmit signals.

The search has begun for an antibody that would destroy these tiny proteins–or ADDLs–thereby preventing the onset of Alzheimer's disease and possibly even reversing the early symptoms. The discovery of ADDLs explains glaring anomalies in the conventional thinking about Alzheimer's, which holds that fragments of amyloid precursor protein, produced by normal neurons, aggregate into sticky, insoluble plaques that damage neurons.

The problem with this theory is that virtually every older person carries some amyloid plaque, but only a few develop Alzheimer's. Conversely, those with Alzheimer's often have relatively few plaques. Another proposed culprit is the presence of tangles of tau protein, which form inside neurons and coincide with the collapse of microtubules that support the cell body and transport nutrients. The tau tangles correlate much better with the disease but tend to appear later, suggesting that they are a consequence, not a cause.

In 1994 Caleb E. Finch, a neurogerontologist at the University of Southern California, attempted to create amyloid plaque by mixing a solution of amyloid precursor protein fragments with clusterin, a substance produced at higher levels in the brains of people with Alzheimer's. The clusterin did not trigger the formation of amyloid plaques, but the resulting solution profoundly disrupted the ability of the neurons to transmit signals.

Finch reported this finding to Grant A. Krafft and William L. Klein, two colleagues at Northwestern University, who set out to discover what was in the solution. Using an atomic-force microscope, they obtained extraordinary pictures of globules no one had ever seen. "They looked like little marbles," Krafft recalls. "It turned out these globules contained only a few of the amyloid peptide building blocks, whereas the long fibrils contained thousands, if not millions, of these subunits."

The three scientists decided to call the substance ADDL, which stands for amyloid beta-derived diffusible ligand. (The molecule is derived from amyloid precursor protein; it diffuses throughout the brain instead of aggregating into fixed plaques; as a ligand, it attaches to receptors on neurons.) Klein developed an antibody that revealed how ADDLs attach to dendrites in the hippocampus, thereby disrupting signals needed to produce short-term memories. And last summer Klein, Krafft, Finch and their colleagues found huge quantities of ADDLs in postmortem brains from people with Alzheimer's, whereas brains from normal patients were virtually free of ADDLs. What is more, they discovered that neurons of mice functioned normally once the ADDLs were removed.

The obvious solution to treat Alzheimer's disease, in Krafft's opinion, is to remove the ADDLs or prevent them from forming. Attempts to eradicate amyloid plaques are misguided, he believes, and any attempt to intervene after neurons have started to die comes too late to do much good. "It's pretty clear to me that we're wasting about 90 percent of the Alzheimer's research budget on things that are worthless," he says.

While crafting their theory, Krafft, Klein and Finch acquired patent rights to ADDLs and formed their own corporation, Acumen Pharmaceuticals, which recently formed a partnership with Merck. "By partnering with Merck, Acumen can get the antibody and vaccine products to market much faster than if we tried to do it by ourselves," Krafft explains.

Merck has committed up to $48 million to Acumen for the right to develop an antibody against Alzheimer's and another $48 million if it succeeds in bringing to market a viable vaccine. That money, plus funding from other investors, will enable Acumen to devise three other ADDL-based strategies for preventing Alzheimer's, as well as diagnostic tests that would reveal early signs of the disease.

Tom Valeo, based in the Chicago area, writes a column on aging for the St. Petersburg Times in Florida.
Source: Scientific American, online at www.sciam.com.
© 1996-2004 Scientific American, Inc. All rights reserved.

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