14 September 2007. Tramiprosate (3-amino-1-propane sulfonic acid, aka 3-APS or Alzhemed), an inhibitor of amyloid-β (Aβ) peptide aggregation, is in clinical testing among other Aβ-modifying therapies. A completed phase 3 clinical trial of the compound has been ruled inconclusive by the FDA (see ARF related news story), and researchers are looking toward an ongoing European trial to give a more definitive thumbs up or down on the treatment in 2009. In the meantime, the compound remains stuck in a painful bind between failure at the statistical level and anecdotal reports by trial participants who swear it helped them (see newspaper story).
In the midst of all this, fundamental questions remain about the mechanism of action and biological activities of tramiprosate. The compound is a patented variant of the amino acid taurine. It was developed to block the actions of endogenous sulfated glycosaminoglycans (sGAGs), which promote Aβ aggregation. sGAGs have long been known to enhance aggregation of tau (Goedert et al., 1996), but no data has been presented about the effects of tramiprosate on this other AD pathology.
That gap is beginning to be filled. New data out this week indicate that, in contrast to its inhibitory actions on Aβ, tramiprosate enhances tau aggregation. The work, from Jesus Avila and colleagues at the Universidad Autonoma de Madrid, Spain, appeared September 6 in Molecular Neurodegeneration, a new open access journal from BioMed Central.
While the drug-induced aggregates did not appear toxic to cells, the report serves as a caution against potential effects of fibril-targeted therapies on tau.
To test if tramiprosate affected tau, first author Ismael Santa-Maria exposed non-neuronal cells that overexpressed tau, or neuronal cells with naturally high tau expression, to the compound. In both cases, the drug (at 100 or 500 micromolar) caused increases in thioflavin S staining, and the quantity of detergent-insoluble tau complexes. Tramiprosate also enhanced aggregation of recombinant tau in vitro.
The tramiprosate-induced aggregates did not alter the microtubule network in cells, and were not toxic to cells, the authors show. The data raise, but do not settle, questions about the possible impacts of the drug on tau in vivo. In an e-mail, Avila told Alzforum that the group is currently testing tramiprosate in mouse models to assess its effects on tau pathology.
A similar cautionary note has been sounded before. Nicotine has long been of interest in AD circles for its ability to reduce amyloid pathology. Recently, researchers showed that nicotine exacerbates tau pathology in the PS1/APP/tau triple transgenic mouse by activating p38-mitogen-activated protein kinase (Oddo et al., 2005 and ARF related news story).
Aβ modifiers are front and center in the quest for new treatments for AD. The amyloid cascade hypothesis puts tau hyperphosphorylation and aggregation downstream of Aβ, which implies that cleaning up the amyloid problem would also deal with tau problems (in AD, not in tau-driven forms of dementia). With compounds lining up to enter the clinic, the new research begs the question of whether researchers, when focusing exclusively on Aβ, might be missing a piece of the puzzle. “We like to emphasize the importance of testing on both types of pathology (amyloid and tau) the potential drugs to be used for AD treatment,” the authors write in their conclusion.—Pat McCaffrey.
Santa-Maria I, Hernandez F, Del Rio J, Moreno FJ, Avila J. Tramiprosate, a drug of potential interest for the treatment of Alzheimer's disease, promotes an abnormal aggregation of tau. Mol Neurodegener. 2007 Sep 6;2(1):17 [Epub ahead of print] Abstract