Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis.

Abstract

Amyloid beta-peptide (Abeta) is a major constituent of senile plaques in Alzheimer's disease (AD). Neurotoxicity results from the conformational transition of Abeta from random-coil to beta-sheet and its oligomerization. Among a series of ionic compounds able to interact with soluble Abeta, Tramiprosate (3-amino-1-propanesulfonic acid; 3APS; Alzhemedtrade mark) was found to maintain Abeta in a non-fibrillar form, to decrease Abeta(42)-induced cell death in neuronal cell cultures, and to inhibit amyloid deposition. Tramiprosate crosses the murine blood-brain barrier (BBB) to exert its activity. Treatment of TgCRND8 mice with Tramiprosate resulted in significant reduction (approximately 30%) in the brain amyloid plaque load and a significant decrease in the cerebral levels of soluble and insoluble Abeta(40) and Abeta(42) (approximately 20-30%). A dose-dependent reduction (up to 60%) of plasma Abeta levels was also observed, suggesting that Tramiprosate influences the central pool of Abeta, changing either its efflux or its metabolism in the brain. We propose that Tramiprosate, which targets soluble Abeta, represents a new and promising therapeutic class of drugs for the treatment of AD.

• Authors: Francine Gervais, Julie Paquette, Céline Morissette, Pascale Krzywkowski, Mathilde Yu, Mounia Azzi, Diane Lacombe, Xianqi Kong, Ahmed Aman, Julie Laurin, Walter A Szarek, Patrick Tremblay
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 28 Issue 4 Pg. 537-47 (Apr 2007) ISSN: 1558-1497 [Electronic] United States
• PMID: 16675063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• GABA Agonists
• Peptide Fragments
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• Taurine
• tramiprosate

Topics

• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics)
• Amyloidosis (blood, pathology, therapy)
• Animals
• Brain (drug effects, pathology)
• Cell Death (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Embryo, Mammalian
• GABA Agonists (blood, pharmacokinetics, therapeutic use)
• Humans
• Mice
• Mice, Transgenic
• Neurons (drug effects)
• Peptide Fragments (metabolism)
• Rats
• Rats, Sprague-Dawley
• Taurine (analogs & derivatives, blood, pharmacokinetics, therapeutic use)