Alzheimer's treatment makes mice brains bleed
Immunization used in halted human trial may weaken blood vessels.
15 November 2002
JOHN WHITFIELD
Alzheimer's attacks blood vessels, as well as brain tissue.
© SPL
Immunizing mice against a condition akin to Alzheimer's disease makes their brains prone to bleeding, researchers have found1. This hints at why cerebral inflammation halted an experimental human vaccine trial early this year.
The link between mouse and human symptoms is still unknown. But both probably stem from the effects of immunization on damaged blood vessels, says the study's leader, Mathias Jucker of the University of Basel, Switzerland.
"These findings are pretty bad for the vaccine," comments neuroscientist Christian Haass of Ludwig Maximilians University, Munich, Germany. "The bleeding is terrible - it could be deadly."
The results suggest that immunization may be more suited to protecting healthy brains than curing diseased ones. Another possibility would be to screen patients for vulnerable blood vessels before vaccination.
But other Alzheimer's experts believe that the different symptoms and side-effects in mice and humans make it impossible to connect this research with the trials. "It would be a giant leap to apply this to an Alzheimer's patient," says Roger Nitsch of the University of Zurich, Switzerland.
This is the first time that bleeding has been seen in any animal or human test of Alzheimer's therapies. "We've never seen anything like this - and we've looked hard for it," comments Dale Schenk, head of research at Elan Pharmaceuticals of South San Francisco, the company behind the trial vaccine.
The mice that Elan use to study Alzheimer's do not have damaged blood vessels, Jucker counters - so one would not expect immunization to affect them in this way.
Despite the setback, Alzheimer's researchers are still optimistic about the prospects for immunization. Most agree that more results are needed from humans for us to truly understand immunization's effects. Follow-up studies and post mortems of the 375 people immunized in the aborted trial should still give us invaluable information.
Beta test
The brains of Alzheimer's sufferers contain deposits of a protein called amyloid beta. These are thought to relate to the brain damage and dementia that are symptomatic of the disease.
Three years ago, researchers at Elan proposed that injecting amyloid beta into the blood triggers an immune response that fights the disease. No one is yet sure how this works.
Tests were spectacular in mice engineered to develop a form of Alzheimer's. Amyloid deposits shrank, and the animals' memories improved. The vaccine was made from a synthetic version of amyloid.
But trials in Alzheimer's sufferers were halted in January, when some patients developed symptoms similar to meningitis and encephalitis. The new finding suggests how this may have come about.
It would be a giant leap to apply this to an Alzheimer's patient
Roger Nitsch
University of Zurich
Jucker and his colleagues injected elderly mice with antibodies against amyloid, rather than amyloid itself. Five months later, the mice had smaller deposits of the protein in their brains. But they also had many small haemorrhages in cerebral blood vessels.
The mice - and most human Alzheimer's patients - have amyloid deposits in the brain's blood vessels, as well as its tissue. Clearing out the protein might weaken these vessels.
Vaccinating people before they get Alzheimer's, or in the very early stages of the disease, might help, as amyloid would not have had time to build up, says Richard Harvey, research director of Britain's Alzheimer's Society.
But if immunized human patients bled, it is surprising that none of them had a stroke, Harvey adds. "I doubt that the bleeding is the whole story". Bleeding may be a second side-effect to put alongside inflammation, agrees neuroscientist Dave Morgan of the University of South Florida.
References
Pfeifer, M. et al. Cerebral hemorrhage after passive anti-AB immunotherapy. Science, 298, 1379, (2002). |Homepage|
© Nature News Service / Macmillan Magazines Ltd 2002
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