Study appearing in PNAS found highest reactivity against oligomeric assemblies of A-beta, like those seen in diseased patients.

Researchers from Stanford University School of Medicine identified antibodies to a about 100 peptides that can aggregate to form plaques such as those found in Alzheimer’s patients have been identified in the blood and cerebrospinal fluid of healthy people. They found that levels of these antibodies decline with age and in Alzheimer’s patients, as the disease progresses.

Published in the July 6 issue of the Proceedings of the National Academy of Sciences, the paper is titled “Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer’s disease.”

The scientists raise the possibility that many of us are carrying antibodies in our blood that could be playing a role in staving off or slowing the progression of Alzheimer’s disease even at a young age. Yet targeting A-beta through immunization or antibodies is a slippery slope there it has a number of different modified, mutated, or metabolized forms. Furthermore, it is believed that more than the plaques themselves, it is smaller aggregations of a few A-beta molecules, called oligomers, which are most toxic to neurons.

Thus the Stanford team conducted a large-scale analysis using samples that ranged in age and disease state to help define different peptides and existing antibodies. They customized microarrays containing close to 100 different peptides each, including A-beta and several of its metabolized, modified, and mutant forms. The peptides were displayed in various degrees of aggregation, and the chip also included peptides capable of aggregating to form other, rare plaque-associated dementias. 

The researchers incubated the chips with blood samples from more than 250 individuals between 21 and 89 years old, some with Alzheimer’s disease and others without it. They observed antibodies targeting many forms and aggregation states of A-beta in both healthy and diseased subjects’ blood, with antibodies to oligomers showing the most immunoreactivity. They noticed that levels of these antibodies declined with age in all samples. And in those with Alzheimer’s, levels also dropped off with advancing stages of the disease.

A follow-on experiment showed that the same antibodies, whether isolated from Alzheimer’s patients or healthy controls, were able to protect freshly cultured mouse neurons in a dish from destruction by A-beta, which is typically highly toxic to these neurons.

Furthermore, the researchers studied samples from vervet monkeys, who like humans develop A-beta-derived brain plaques as they age. Past experiments showed that immunizing older monkeys with A-beta substantially cleared their plaques. In this study the Stanford team obtained blood samples extracted from those monkeys before and after immunization and compared levels and diversity of relevant antibodies in pre and postinoculation samples.

Interestingly, in both monkeys and healthy human subjects the investigators also detected antibodies to the peptides associated with rare plaque-associated dementias. Although these peptides’ amino-acid sequences are nothing like that of A-beta’s, antibodies against them occur even in the blood of healthy participants who have never been diagnosed with any of those rare dementias. 

The researchers think this may mean that at least some antibodies they’ve isolated target not plaque-generating peptides’ amino-acid sequences but rather a common shape these molecules assume in the early, oligomeric stages of their aggregation.

The researchers suggest that a future step may be to immunize Alzheimer’s patients with peptides that, unlike A-beta, have amino-acid sequences different from any of those occurring naturally in the human body. The hypothesis is that that by virtue of their 3-D similarity to A-beta, antibodies to A-beta oligomers will be generated as well as they begin to aggregate.

If a therapeutic benefit of amyloid-beta antibodies can be confirmed in Alzheimer’s, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward the disease, the authors write.

The Stanford team has filed provisional patent applications covering its technology. Use of this tool could help monitor clinical trials using immunotherapeutics, notes Tony Wyss-Coray, Ph.D., associate professor of neurology and neurological sciences and the paper’s senior author. “With our microarray, it would be possible to see whether certain types of antibodies correlate better with cognitive benefits than others do.”

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