Untangling Alzheimer's by Paring Plaques

4 August 2004 (All day)

Double trouble. ß-amyloid plaques (diffuse black structures) and tau tangles (open, black circles) mar this slice of mouse brain.

Experiments with mice hint that targeting one of the two molecular aggregates gumming up brains with Alzheimer's disease also rids tissue of the other, as long as treatment starts early enough. This finding and a recent analysis of an interrupted Alzheimer's vaccine trial in people have brought new life to the idea of immunotherapy for the debilitating disease.

An ongoing debate in Alzheimer's research centers on the relative importance of brain plaques (extracellular clumps of a protein fragment called ß amyloid) and tangles (filaments of the protein tau that form inside neurons). Researchers have had difficulty testing the roles of plaques and tangles because no one had created mice that develop both--until last year, when neuroscientist Frank LaFerla of the University of California, Irvine, and colleagues engineered mice that develop plaques and tangles in the same brain regions as the brains of people with Alzheimer's disease do.

In the new work, the team injected antibodies against ß amyloid into the hippocampus of their transgenic mice when the animals were 1 year old. Three days after the injection, plaques in the injected animals had disappeared. Between 5 and 7 days after the injection, tau, which had aggregated within neurons but not yet formed tangles, also had melted away. Additional experiments with a different set of engineered mice suggested that the antibodies can't budge tangles once they have formed, however.The rodent work seems to mirror recent findings in autopsied brains from people involved in a 2002 vaccine trial for Alzheimer's disease, which had been abruptly halted when a small percentage of patients developed brain inflammation. Last month, at the 9th International Conference on Alzheimer's Disease and Related Disorders in Philadelphia, Pennsylvania, Sid Gilman of the University of Michigan, Ann Arbor, described the brains of four people with mild to moderate Alzheimer's disease who had received the vaccine and subsequently died from unrelated causes. Although each brain showed an almost complete lack of ß amyloid, the tangles remained.LaFerla's work "goes hand-in-hand with the vaccine trial," says neurobiologist Virginia Lee of the University of Pennsylvania in Philadelphia. The mouse and human data suggest that a vaccine would be most therapeutic if researchers treat patients in very early stages of the disease, before tau forms tangles. Still, Lee admits, that remains a bit of a "pipe dream," because such patients can't yet be identified. Nevertheless, the vaccine strategy isn't dead yet: Biotech companies are redesigning ß amyloid vaccines to make them safer and are considering new clinical trials.

Related sites
Frank LaFerla's UCI lab
NIH's Alzheimer's site
9th International Conference on Alzheimer's Disease and Related Disorders

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