Targeting soluble Aβ peptide with Tramiprosate for the treatment of brain amyloidosis

Amyloid P-peptide (A beta) is a major constituent of senile plaques in Alzheimer's disease (AD). Neurotoxicity results from the conformational transition of A beta from random-coil to beta-sheet and its oligomerization. Among a series of ionic compounds able to interact with soluble A beta, Tramiprosate (3-amino-1-propanesulfonic acid; 3APS; Alzhemed (TM)) was found to maintain A beta in a non-fibrillar form, to decrease A beta(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 (similar to 30%) in the brain amyloid plaque load and a significant decrease in the cerebral levels of soluble and insoluble A beta(40) and A beta(42) (similar to 20-30%). A dose-dependent reduction (up to 60%) of plasma A beta levels was also observed, suggesting that Tramiprosate influences the central pool of A beta, changing either its efflux or its metabolism in the brain. We propose that Tramiprosate, which targets soluble A beta, represents a new and promising therapeutic class of drugs for the treatment of AD. (c) 2006 Elsevier Inc. All rights reserved.