New ways to knock Alzheimer's on the head
Sun, 15th Feb 2009
Download as mp3
Scientists have uncovered two new approaches to blocking the progression of Alzheimer's disease. The two separate studies, one from a Belgian group of researchers from the Catholic University of Leuven and published in the journal Science and the other from an NIH team in Bethesda, US and published in PNAS, focus on the mechanism by which a protein called beta amyloid, which builds up in the brains of Alzheimer's patients, is formed and how it harms cells.
Histopathogic image of senile plaques seen in the cerebral cortex in a patient with Alzheimer disease of pre-senile onset. Silver impregnation. © KGH
In the Science paper Amantha Thathiah and colleagues used a genetic technique to look for chemical messengers that, when added to cells, increased beta amyloid production. Using this approach they were able to home in on a signalling molecule called G protein-coupled receptor 3 (GPR-3), which turns on an enzyme called gamma-secretase, which in turn produces beta amyloid. As the team expected, turning off the molecule reduced beta-amyloid production whilst boosting its levels increased beta-amyloid. Encouragingly, GPR-3 is only expressed in the brain, which means it might be possible to engineer a drug designed to target selectively this receptor, thus minimising the side effects, which have plagued earlier anti-Alzheimer's drug strategies.
Meanwhile, the PNAS paper by Juan Carlos Diaz and his colleagues tests the theory that the beta-amyloid that builds up in the brain damages nerve cells by forming new pores in the nerve cell membranes. These pores allow calcium to flow into the cell, causing it to become over-excited and die. To combat the problem the team have engineered two new drug molecules, which have been designed specifically to block up these hypothetical pores.
Working with cultured cells the team added beta amyloid alone or beta amyloid plus one of the two blocking drugs and used sensitive measuring techniques to monitor the flow of calcium into the cells. Cells incubated with just beta amyloid showed high levels of cell death preceeded by calcium flowing in. But cells treated with the two new compounds showed equivalent survival rates to untreated control cells.
"If the neurotoxic mechanism for amyloid beta is the formation of toxic calcium channels, then compounds that block the channels can logically be considered candidate Alzheimer's drugs," says the researchers.
“Small molecule blockers of the Alzheimer Aß calcium channel potently protect neurons from Aß cytotoxicity,” by Juan Carlos Diaz, Olga Simakova, Kenneth A. Jacobson, Nelson Arispe, and Harvey B. Pollard; PNAS Early edition"The Orphan G Protein-Coupled Receptor 3 Modulates Amyloid-Beta Peptide Generation in Neurons," by A. Thathiah; K. Horré; M. Vanbrabant; B. De Strooper; F. Coun; V. Baekelandt; F. Coun; K. Spittaels; M. Hoffmann; M. Staes; A. Cohen; D. Pollet; P. Merchiers; D.F. Fischer; A. Delacourte; Science 323; 13 February 2009; pp. 946-951