Cocaine use may damage dopaminergic system.

Ever since a phase II trial of Elan and Wyeth’s experimental vaccine for Alzheimer’s disease (AD) was halted in Jan, 2002, after some patients developed meningoencephalitis (Lancet Neurol 2003; 1: 3), researchers at the two companies have been racing to find out which part of the synthetic protein AN-1792 was responsible for triggering the inflammatory response. On Nov 9 they reported at the Society for Neuroscience meeting (New Orleans, LA, USA) that a fragment of AN-1792 can induce the production of antibodies to amyloidpeptide (A ) deposits in brain tissue of patients with AD without triggering inflammation, raising hopes that a modified form of AN-1792 still holds promise as a vaccine. AN-1792 contains a form of A that is 42 amino acids in length, which proved effective in early trials at clearing A plaques from the brains of patients with AD. So, Mike Lee (Elan, San Francisco, CA, USA) and colleagues made a series of 10-amino acid fragments of AN-1792, to find out which portion is recognised by the patient’s antibodies, producing the therapeutic effect. They found that all patients who raised antibodies to AN-1792 actually raised antibodies to one very specific part of it—the tail end of A . That finding contradicted earlier studies that had suggested that patients’ antibodies only recognised aggregates of AN-1792, thought to resemble the clumps of A that occur in AD brains. They then looked to see if the antibody response in those patients who had the inflammatory response differed from those who did not, and found that it was identical. That suggested that some other immune mechanism had triggered the meningoencephalitis. “The meningoencephalitis was supposed to be caused by the auto-reactive Th1-type T cells”, says Hideo Hara of the National Institute for Longevity Sciences in Aichi, Japan, adding that Th2-type T cells are needed to raise the antibody response. “If the team . . . has developed a vaccine with the new fragment of the protein plus adjuvant that induces only the Th2-type T cells and does not induce Th1-type T cell immune responses, it will work without the side-effects of meningoencephalitis”, he says. Hara is leading a team working on an oral vaccine that he believes will bypass the Th1 T cell-mediated response entirely. They have shown that their approach, which uses an adenoassociated virus as a vector, is effective in mice, and are now testing it in ageing monkeys. “The production of antibodies lasts at least 6 months after only one oral administration, which may be of benefit for the patients because they do not need to receive frequent intramuscular injections”, says Hara. He adds that it may be safer than injecting viral vectors into muscles, because the turnover of epithelial cells lining the gut is so rapid that the vector cannot remain in the body for long. Laura Spinney Update on Elan vaccine for Alzheimer’s disease