Another enzyme target in Alzheimer's
a promising new target for Alzheimer's disease drugs, if research
conducted in Germany is borne out in additional study.
Researchers from the University of Mainz in Germany found that alpha-secretase plays a key role in the formation of the amyloid deposits or plaques that are laid down in the brains of Alzheimer's sufferers and are a hallmark of the disease.
The beta and gamma secretases have already been the subject of considerable research, with a number of antagonists of these enzymes coming into clinical development from the likes of GlaxoSmithKline, Amgen, Merck & Co, AstraZeneca and Bristol-Myers Squibb.
The latest research, published in the Journal of Clinical Investigation (15 May), now suggests that alpha-secretase could also be a valid target for the disease.
The plaques in Alzheimer's disease are made up of amyloid beta-peptide (AB peptide) so strategies for a pharmacotherapy aim at reducing the generation of this peptide from the breakdown of amyloid precursor protein (APP).
Beta and gamma secretase have been the main targets of treatment as they are directly responsible for AB peptide generation, cleaving APP at each end of the molecule. Alpha-secretase cleaves within the AB peptide domain of APP, and theoretically should prevent AB peptide generation.
"In the APP processing pathway, alpha-secretase cleavage of APP generates an alternative breakdown product of the protein that cannot generate AB peptide," said the authors of the study.
The researchers used a mouse model deficient in or overexpressing the gene ADAM10, which codes for alpha-secretase protein. They found that moderately increased expression of ADAM10 in mice reduced AB peptide formation, prevented plaque formation, and, from a functional standpoint, provided improvement in long-term potentiation - the ability of nerve cells to conduct stronger, repeat signals in a manner akin to learning - and cognitive impairment.
On the other hand, mice lacking ADAM10 had increased number and size of amyloid plaques, providing additional evidence that alpha-secretase might be a useful therapeutic target for AD. It also suggests that impairment of this enzyme might underlie some forms of the disease.
