Potential therapeutics of Alzheimer's diseases: New insights into the neuroprotective role of trehalose-conjugated beta sheet breaker peptides

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure. The conversion of the amyloid-beta (A beta) peptide into soluble oligomers has recently become recognized as playing a key role in AD pathogenesis. Thus, prevention and therapeutic strategies against AD focus on modulating A beta levels aiming also at stabilizing A beta's monomeric status or inhibiting the peptide's self-assembly. Peptide-based inhibitors may provide a reasonable alternative to chemical small molecules. We report herein further insights into the neuroprotective action of two trehalose-conjugated peptides able to counteract the A beta's oligomers associated neuronal toxicity. In addition, the Trehalose-Succinyl-LPFFD-NH2 (Th-Succ-LPFFD-NH2) and Ac-LPFFD-Trehalose (Ac-LPFFD-Th) derivatives protect neuronal cells from excitotoxic insult mediated by NMDA and evoke by themselves pro-survival signal pathways as an additional cell protective action. UHPLC-HRMS experiments suggest that a possible step associated to the neuroprotective mechanism involves the cell uptake and/or a membrane interaction of the studied peptides.