By David N. Leff

Vaccination against Alzheimer¿s disease?

Starting with smallpox over two centuries ago, immunization has been given to forestall or mitigate infectious diseases. In recent decades, HIV and malaria vaccines have been top targets. But what about Alzheimer¿s (AD) ¿ a noninfectious disorder?

¿People in this whole area the past year and a half,¿ observed AD-focused research neurologist David Holtzman, ¿have been excited by the prospect.¿ He added that Elan Pharmaceuticals Inc. [in South San Francisco] ¿is already going forward, and is conducting Phase I clinical trials of active immunization against the amyloid-beta peptide in humans. Their research is actively being pursued for possible prevention and/or treatment of AD. Whether it works or not we don¿t know.¿

The amyloid-beta (A-b) peptide is not spawned by a virus, bacterium, or fungus, yet it¿s in the popular cross-hairs of a monoclonal antibody aimed at removing it.

¿Amyloid-beta is in all of our bodies,¿ Holtzman pointed out. ¿All of us humans make it constantly in pretty good levels during our whole life. We don¿t know, unfortunately, what it¿s doing in healthy bodies. For some reason in AD, some of the amyloid-beta that¿s in the brain begins to change conformation and aggregate.¿

That clumping turns A-b from an apparently innocuous molecule into the perpetrator of senile neuritic plaques ¿ the pathological hallmarks of AD that wrap around the dying nerve endings of the disease.

Holtzman, who holds an endowed chair in neurology at Washington University in St. Louis, is senior author of a paper in today¿s Proceedings of the National Academy of Sciences (PNAS), dated July 3, 2001. Its title: ¿Peripheral anti-A-b antibody alters CNS [central nervous system] and plasma A-b clearance and decreases brain A-b burden in a mouse model of Alzheimer¿s disease.¿

¿The most important finding of this report,¿ Holtzman told BioWorld Today, ¿is its suggestion that antibodies to the amyloid-beta peptide that builds up in AD brain appear to reduce the pathology when given over time to this mouse model. The point of our paper is that it really doesn¿t appear to require the antibody getting into the brain.¿

Near-Human Mice Mimic AD Stigmata, Symptoms

That mouse is a scaled-down, living replica of Alzheimer¿s pathology and symptoms. ¿It¿s an animal that expresses the human form of the APP protein ¿ precursor of the A-b peptide ¿ with a mutation that eventuates in familial AD. This results in an age-dependent formation of amyloid-beta deposition in the mouse brain, much similar to what occurs in the human AD brain. So when the mice are born,¿ he continued, ¿and up until they reach a certain age, their brains look pretty normal. You don¿t see any AD-like pathology. Then, beginning at six to seven months of age,¿ Holtzman continued, ¿they begin getting amyloid-beta deposits and neuritic plaques in the brain.¿

In two in vivo experiments, the co-authors tested the effects of pure, monoclonal antibody to amyloid-beta peptide, supplied by Eli Lilly & Co., of Indianapolis.

¿In the first trial,¿ Holtzman recounted, ¿we gave that monoclonal antibody intravenously to animals when they were young. They were producing the human amyloid-beta peptide in their brain and in their blood. First thing we did was measure how much of the A-b peptide was in their blood, which normally turns out to be 150 picograms per milliliter. Then we found when we administered this antibody directed at the amyloid-beta peptide, the concentration of that peptide in the blood dramatically increased. Within hours, it was up to 1,000 times higher than its normal level.

¿That A-b peptide now shunted from brain to blood, is all bound to the antibody. We knew that in these animals A-b in their bodies is all being generated in their brains. This meant that that marked increase in the A-b in their blood was coming from their brain.

¿In the second controlled experiment,¿ Holtzman went on, ¿we injected the antibody into the animals¿ abdomen chronically over five months ¿ beginning at a time point when there was no AD-like pathology in their brains. Then we asked: When they¿re older how much pathology will there be in the brain? The animals injected for five months with the antibody then had less pathology then the control mice, given saline or dummy treatment.

¿One obvious interpretation of this result,¿ he pointed out, ¿is that the antibody was somehow causing that effect. Then we asked: Of the antibody that we¿re injecting, how much is getting into the brain, and is it binding to neuritic plaque? The amount getting in proved to be very small ¿ less than 0.1 percent of what we injected into their bloodstream, and we found far fewer plaques in antibody recipients than in control mice.¿

As regards an eventual human vaccine against AD, Holtzman sees potential advantages in passive vaccination, rather than the active version being tested by Elan and others.

Which Immunization: Active Or Passive?

¿Our work obviously suggests,¿ he said, ¿that maybe a passive approach, not an active one, is another avenue to investigate. One of its essential advantages is that you would know exactly what vaccine you¿re giving, how much and when you want to give it, and without essential complications of an immune response that you¿re inducing in people that¿s going to be different with every person.¿

He explained: ¿If I gave an injection of measles vaccine to you and to another person, your antibody and cellular response to that vaccine is going to be different to that of your neighbor. Some people develop a much more robust response, some a weaker response, some a response to other associated antigens, and some can get an autoimmune disease.

¿The advantage of passive immunization,¿ Holtzman summed up, ¿is that humanized monoclonal antibodies are already being used for other human diseases They¿re known to be safe, and you know exactly what you¿re giving to people. If there¿s any doubt or side effect,¿ he concluded, ¿then you stop it.¿

¿What we have discovered,¿ observed co-author Steven Paul, group vice president at Lilly Research Laboratories, ¿is that this particular antibody can be administered into the bloodstream, and not necessarily gain access to the brain, while directly reducing plaques. This suggests a new mechanism by which certain anti-amyloid antibodies could be useful in preventing or treating Alzheimer¿s.¿

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