By David N. Leff
Vaccination - as we know it - takes aim at infectious organisms that invade the body. Vaccines draw beads in their cross hairs on viruses, bacteria or antigens in parasites, to be counterattacked by immune-system antibodies.
So the idea of a vaccine against Alzheimer's disease (AD) seems somehow counter-intuitive. The amyloid plaques and tangles that mark the aging AD brain obviously don't arise from infectious pathogens. Rather, they derive from a rogue molecule called amyloid-beta (Ab), which breaks off from a mother molecule - the amyloid precursor peptide - to poison the failing AD neurons that wreak loss of memory, cognition, orientation and eventually dementia.
Today's issue of Nature, dated Dec. 21, 2000, features not one, but three research papers dedicated to the proposition that vaccinating the brains of mice against Ab may treat the symptoms of AD. Signaling the reach of this concept is the fact that each article comes from a different country - the U.S., Canada and Scotland.
A fourth country, Ireland, launched this crusade a year ago. "On July 8, 1999," recalled neuroscientist David Morgan, at the University of South Florida in Tampa, "Nature published a study indicating that neurobiologists at Elan Corp. plc in Athlone, Ireland, by vaccinating their transgenic AD mice with amyloid, prevented accumulation of plaques in their brains."
Morgan, who directs his University's Alzheimer Research Laboratory, is lead author of the paper in today's Nature titled: "Ab peptide vaccination prevents memory loss in an animal model of Alzheimer's disease."
"Our principle finding," he told BioWorld Today, "is essentially contained in that title. That's the real key. We actually started the study," he continued, "with the widely held hypothesis that a vaccine would make these mice worse, not better. This prediction was based on the fact that the activation of inflammatory processes by the immune system is thought to cause some of the damage in AD. So that was our prediction, and we actually tested the animals at an age before they would develop the amyloid toxicity." He observed that "scientists have been able to generate AD-transgenic mice, which, as they aged, developed amyloid plaques in their brains just like Alzheimer patients do. However," he added, "demonstrating consistent memory loss in these AD surrogate animals has proven difficult."
Nuts And Bolts Of Anti-AD Immunization
Formulating the vaccine, Morgan explained, "is very simple. We looked up in our chemical supply catalogue and ordered synthetically produced amyloid-beta peptide. We dissolved it in water, added salt, let it sit overnight, then mixed it up with Freund's adjuvant and injected it subcutaneously into our AD mice.
"Amyloid is present in the brain, which is immuno-privileged," Morgan went on, "and for some reason you don't get antibodies produced against the amyloid when it's just in the brain. But when you inject it peripherally, subcutaneously, in the presence of adjuvant - which makes the animal think there's an infection going on - that actually provokes the immune system to make antibodies.
"The antigenic target is the amyloid-beta peptide, in particular its fibril. We used the Ab 1-to-42-amino-acid sequence as our antigen. The antibody is directed against the first 10 amino acids. There's evidence that it targets them for phagocytosis and removal by microglia in the brain."
To test their vaccinated and naive mice for memory loss, Morgan's team resorted to the now-classic radial-arm water maze. It consists of a circular swimming pool full of opaque water, with a submerged platform below the surface, located in one of six different pie-shaped sectors each day. "After training the mice to find the hidden platform and its exit locations," recounted Gary Arendash, the Tampa paper's final author, "we waited 30 minutes to get a measure of short-term memory, then let them search for the platform again. It's like going to the mall and parking your car every day in a different location," Arendash said. "Can you remember the new parking spot each day?
"We set up a task where we give the animals five trials in a day," Morgan recounted. "The first trial they don't remember where the platform is so they make a number of errors. Then they figure out where it is, and by trial two at 12 months, all the animals did well. And that's where we thought there might be a problem with the vaccine because of inflammation occurring in their brain. It turned out not to be an issue. So then we continued treating the animals until 15 months. At that age we had previously shown that these mice show memory deficits. And the control transgenic mice don't learn it at all.
"So there's a big difference in those animals between 12 and 15 months of age. They've developed a memory loss typical of progressing AD. The nontransgenic mice, which don't have any amyloid in their brains, continue to learn."
At the University of Toronto's Center for Research in Neurodegenerative Diseases, its director, Peter St George-Hyslop, is co-senior author of the paper in today's Nature titled: "Ab peptide immunization reduces behavioral impairment and plaques in a model of Alzheimer's disease."
"They use a different mouse model," Tampa's Morgan observed, "and a different behavioral task, and tested a very similar vaccine to ours. But even though everything was different, they still found, qualitatively, essentially the same results. That is, their vaccine too protected the mice from developing memory deficits."
St George-Hyslop said, "Not only were we able to clean up the brain tissue, but we also prevented the behavioral consequences of Alzheimer's. Obviously," he added, "It is more important that a treatment or prevention in humans be able to block the clinical dementia."
Elan's Vaccine Finishing Phase I Trials; Phase II Next
Neuroscientist Richard Morris, at the University of Edinburgh in Scotland, is senior author of today's third Nature article.
He and his co-authors were testing the same mice that Elan uses. Morris made the point, "Patients in the early stages of AD are often quite good at remembering events from early on in their lives. It's keeping track of things from more recent times that really poses their problem. Tests have to distinguish between short- and long-term memory. Easy enough in humans, but what about rodents?"
"Our Phase I trials of the AD vaccine," Elan spokesman Max Gershenoff told BioWorld Today, "have approximately 100 patients enrolled at centers in the U.S. and UK. Phase II clinical studies are expected to start late in 2001."