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

Proteoglycans are a prominent constituent of Aβ deposits, and  are implicated in Aβ fibril formation.The sulfated glycosaminoglycans (GAGs), a component of the proteoglycans, contribute to Aβ fibrillogenesis by promoting the transition of Aβ peptide from a random-coil to a beta-sheet rich conformation and protecting the fibrillar protein from proteolysis.  It is believed that fibrillar- Aβ is toxic to neurons and is an intermediate in the formation of Aβ plaques. In previous studies the authors screened a series of low-molecular weight molecules that mimic the ionic properties required for the binding of GAGs to Aβ; thus these low molecular weight molecules are GAG- mimetics that interfere with fibrillization of Aβ peptide. One of these  molecules- Tramiprosate (also known as homotaurine) is anti-fibrillogenic, provides neuroprotection against Aβ-induced neurotoxicity in neuronal and mouse organotypic hippocampal cultures, and reverses Aβ-induced long-term potentiation (LTP) inhibition in rat hippocampus. The overarching aim of this study was to determine PK properties of Tramiprosate and test its efficacy in reducing brain Aβ peptide levels and Aβ plaque load in the TgCRND8 mouse model of AD-like brain amyloidosis.  The data showed that Tramiprosate maintained Aβ in a non-fibrillar form, decreased Aβ42-induced cell death in neuronal cell cultures, and inhibited amyloid deposition. In addition, Tramiprosate was found to cross the murine blood-brain barrier (BBB) to exert its activity. Treatment of TgCRND8 mice with Tramiprosate resulted in significant reduction (∼30%) in the brain Aβ plaque load and a significant decrease (∼20–30%) in the cerebral levels of soluble and insoluble Aβ 40 and Aβ 42 peptides. A dose-dependent reduction (up to 60%) of plasma Aβ levels was also observed, suggesting that Tramiprosate influences the central pool of Aβ changing either its efflux or its metabolism in the brain.