In the year two thousand we made great strides towards our goal of eradicating the suffering from Alzheimer's disease.
The brains of people with AD contain plaques of a peptide called b-amyloid, which many researchers believe causes dementia. b-amyloid is formed when a protein called amyloid precursor protein (APP) is broken down by the enzymes b- and g-secretase. In 1999, a group from Elan Pharmaceuticals demonstrated that vaccination with the b-amyloid peptide prevented plaque development in a mouse model of AD. However, at this stage it was not known if this reduction in the development of plaques would actually translate into improved cognitive function.
Three studies published in Nature at the end of last year suggest that this may, in fact, be the case. In the first paper, Chen et al., using a murine model of AD, provided evidence of age-dependent learning deficits that are associated with increasing levels of b-amyloid peptide. In the other two papers, the researchers examined, also in murine models of AD, the effects of immunization with the b-amyloid peptide on learning and memory, as well as on brain damage. Similar to the previous study, they both found a reduction in the formation of amyloid deposits in the brains of these mice. Perhaps more importantly, they show that immunization also allows the mice some protection from the learning deficits that normally accompany plaque formation.
Janus et al., show that when the mice are immunized with the b-amyloid peptide in the b-pleated sheet conformation that is eventually deposited, they produce antibodies that are specific to that particular conformation. What results is a reduction in the formation of plaques and the number of amyloid fibrils, without a significant reduction in the overall levels of b-amyloid peptide. This suggests that there may be a more toxic form of b-amyloid that can be specifically targeted without reducing, the potentially less harmful, soluble form of the protein. However, the second group used a more soluble form of the peptide and still found reductions in the proportion of the brain's neocortical and hippocampal regions that is covered by amyloid plaques. Both groups suggest that by only slightly reducing the deposition of b-amyloid we may protect the brain against the progression of AD.
The next step will be for pharmaceutical manufacturers to conduct preliminary trials on the safety of the vaccination, before larger scale testing can begin on its therapeutic effectiveness. The researchers believe clinical trials could begin on human subjects within the year.
References
- Chen G, et al. Nature 2000;408:975-79.
- Janus C, et al. Nature 2000;408:979-82.
- Morgan D, et al. Nature 2000;408:982-85.
