— A pioneering drug treatment has restored memory function in mice with Alzheimers disease.
The treatment worked on mice whose brains were already clogged with the amyloid plaques blamed for the irreversible brain damage characteristic of the disease. The researchers hope the same drug will one day treat humans with late-stage Alzheimers.
Most existing treatments and vaccines are aimed at destroying the plaques, or stopping any more from forming. The new treatment targets a different part of the brain, and appears to have an effect whether or not the plaque is already there.
Michael Shelanski at Columbia University in New York, US, and colleagues tested a treatment aimed at helping brain cells dispose of unwanted or over-abundant proteins.
Earlier studies had demonstrated that an enzyme responsible for protein disposal called ubiquitin C-terminal hydrolase L1 (Uch-L1) plunges when healthy brain cells are exposed to the amyloid beta plaque protein, which is abundant in people with Alzheimers.
Perhaps as a result of this, proteins usually destined for destruction accumulate in the brains and cells of Alzheimers patients, suggesting that although they were marked for disposal, the process was disrupted.
So Shelanski wanted to see what would happen if they provided extra supplies of the missing enzyme, both in brain tissues grown in the lab, and in mice with the equivalent of Alzheimers disease.
The team exposed mouse brain slices to amyloid-beta protein, which reduced the neurons ability to transmit signals. But, by adding extra Uch-L1, the deficits in nerve transmission were reversed. The same happened in brain slices from mice genetically engineered to produce too much amyloid-beta protein.
The team then used mice that were bred to produce the rodent equivalent of Alzheimers disease. When these mice received extra Uch-L1, via an injection into the abdomen, their learning ability as measured by standard tests improved markedly.
Moreover, their abilities improved without any changes in the amount of amyloid-beta protein in their brains.
Were hoping that this treatment can help people who have a lot of plaques in their brain already, or perhaps in combination with other compounds that reduce amyloid-beta, says Shelanski.
However, he says that the treatment as it stands is not ideal, as the extra Uch-L1 has to be given by injection into the abdomen. So instead, the team is screening thousands of molecules which could be given as a pill, but which also raise levels of the enzyme.
The approach might work best in people whose brains still contain soluble rather than solid deposits of amyloid beta protein, as disruption of memory formation by the soluble form is reversible, comments Brian Austen, who studies amyloid protein at St Georges University of London, UK.
But brain cells damaged by the solid plaque might not be recoverable, Austen says. The approach would not help patients get back their missing neurones, but it would prevent any further memory loss.
The UK Alzheimers Society hailed the arrival of a potential new drug and new target for treatment. Currently, theres only one type of drug available, and this only stabilises symptoms for a limited period, said a spokeswoman. But research on the new approach is still in the early stages [...] so further trials and research are urgently needed.
Journal reference: Cell (DOI: 10.1016/j.cell.2006.06.046)