Stopping Alzheimer’s: Antibody thwarts disease in mice

Amyloid beta, the waxy protein that litters the brains of Alzheimer’s patients, is like a criminal with many arrests but no convictions. Studies have implicated amyloid plaques in the disease, but nobody has proved that they cause it.

Now, scientists working with mice report that antibodies tailor-made to attack amyloid can wipe it out and reverse an experimental version of Alzheimer’s disease if the intervention begins early enough. What’s more, removing amyloid rubbed out its partner in crime, a protein called tau that collects in tangles inside brain cells. The work appears in the Aug. 5 Neuron.

This study “provides the strongest experimental evidence to date” that amyloid is the ringleader of Alzheimer’s disease, says coauthor Frank M. LaFerla, a neuroscientist at the University of California, Irvine. LaFerla suspects that amyloid collaborates with tau to kill neurons and trigger the confusion and memory loss that mark the disease.

In their tests, LaFerla and his colleagues used mice genetically engineered to make excess amyloid and tau. The researchers then injected antibodies against amyloid into the animals’ brains.

Three days later, the researchers could not find any amyloid plaques in the brain region targeted by the injection, but neurons there still contained tau tangles. After 2 more days, these tangles were cleared too.

“This is an important paper,” says David Morgan, a neuroscientist at the University of South Florida in Tampa. Knocking out amyloid plaques and subsequently seeing a decrease in tau indicates that the plaques promote tau tangles in the brain, he says.

In further experiments, on mice with an even greater genetic predisposition to developing tau tangles, LaFerla’s group collected less-promising data. In those tests, antibody injections reversed tau accumulations in the first stages of their formation but not after the protein had added phosphate groups.

“This shows that there is an early window of time during which clearance of amyloid by antibodies is accompanied by clearance of tau,” says neurologist Sam Gandy of the Thomas Jefferson University in Philadelphia.

Morgan says the finding indicates that antibody therapy might work best if administered early in the disease.

Furthermore, patients might need to continue treatment for years. In the mouse experiment, the amyloid-clearing antibodies had broken down and amyloid plaques had reappeared by the end of a month. Tau buildup followed 15 days later, LaFerla and his colleagues report. The course of events suggests that there is an ongoing cycle of manufacture and disposal of amyloid in the brain, and that this cycle becomes imbalanced in Alzheimer’s patients, LaFerla says.

He says that the amyloid-tau link could be mediated by proteasomes, which are protein configurations that act as trash collectors inside cells. Normally, proteasomes nab excess tau and dispose of it. Suspecting that amyloid in the cells blocks this process, the researchers tracked tau accumulations and found that tau was cleared more effectively after amyloid was depleted.

Adding to the researchers’ optimism is the absence of inflammation in the brain following the antibody injections. In an earlier study, in which scientists vaccinated Alzheimer’s patients with amyloid, some patients developed brain inflammation (SN: 7/15/00, p. 38: Possible Alzheimer’s vaccine seems safe; 3/16/02, p. 174: Available to subscribers at Alzheimer’s disease vaccine abandoned). That study was stopped after a few injections per patient.

Even so, the vaccination might have had some benefit. Swiss researchers reported at an Alzheimer’s meeting in Philadelphia in July that some patients who had been given the vaccine developed high antibody concentrations. Two years after receiving injections, these people showed less cognitive decline than did patients who had received inert injections.

Elan, the Dublin-based pharmaceutical company that developed the vaccine, is now pursuing the antibody approach to develop an Alzheimer’s treatment.

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