Familial Alzheimer disease

An experimental vaccine directed against amyloid, a protein implicated in Alzheimer's disease, has shown promise in animal trials (Nature 1999;400:173-7). The vaccine may lead to an effective treatment.

Scientists at Elan Pharmaceuticals developed a transgenic mouse model of Alzheimer's disease by injecting the rodent with a mutant form of the human amyloid precursor protein. The mutant amyloid precursor protein gene, which occurs in a number of familial forms of Alzheimer's disease, leads to an overexpression of the amyloid [Beta] peptide, the principal constituent of amyloid plaque in the disease.

Amyloid plaques consist of insoluble aggregates of amyloid protein and are thought to be involved in neuronal cell death.

The transgenic mice developed amyloid plaques in their brains in a manner specific to age and brain region, mimicking the changes seen in human forms of Alzheimer's disease.

The researchers then sought to see if immunisation with a fragment of amyloid protein would modify the disease in their affected mice. Accordingly, mice were immunised with a 42 amino acid segment of the amyloid B protein.

One group of mice was immunised at 6 weeks of age, when the neuropathological hallmarks of Alzheimer's disease are not yet present, and a second group at 11 months of age, when amyloid deposition is already prominent. Two main experiments were then conducted. In the first experiment (with the mice immunised at 6 weeks old), three control groups were used for comparison: one group received saline vaccinations, a second was left untreated, and the third was immunised with another plaque associated protein (serum amyloid protein).

At the age of 13 weeks, the groups vaccinated at 6 weeks were killed and their brains examined. Seven out of the nine mice treated with the [Beta] amyloid protein had no detectable plaques, whereas the other groups showed age related plaque accumulation.

In the second experiment (with the mice immunised at 11 months old) two control groups from the same litter were left untreated. At 18 months the vaccinated mice showed significantly less plaque formation than their 18 month old controls. They also had less gliosis and neuritic dystrophy. Even more striking, however, was the finding that these mice also had less plaque formation than younger untreated control mice, those at 12 months old.

This suggests that immunisation with the amyloid [Beta] protein facilitated the removal of amyloid plaque, probably by an antibody mediated immune attack.

Commenting on the study, Dale Schenk, the chief investigator on the project, said: "When we examined that group at 18 months ... we expected to see widespread brain pathology [but] it had been halted in its tracks.

"The brain tissue looked essentially like [that of] the original 11 month old animal and in fact looked somewhat better. This suggested to us that the vaccine had potential for treatment."

The researchers said that the vaccine did not have any detectable side effects in mice.

Although the results are promising, it is not known if the findings are applicable to humans. Whether amyloid deposition is the cause or the effect of Alzheimer's disease is still widely debated.

Furthermore, although the mice developed plaques, they lacked other features of the disease, such as neurofibrillary tangles, and cognitive decline.

A spokesman for Elan Pharmaceuticals said that the company plans to submit an application to the US Food and Drug Administration and hopes to begin human clinical trials by the end of next year.

COPYRIGHT 1999 British Medical Association
COPYRIGHT 2000 Gale Group