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Poly(trehalose) Nanoparticles Prevent Amyloid Aggregation and Suppress Polyglutamine Aggregation in a Huntington’s Disease Model Mouse

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posted on 2017-08-18, 19:18 authored by Koushik Debnath, Nibedita Pradhan, Brijesh Kumar Singh, Nihar R. Jana, Nikhil R. Jana
Prevention and therapeutic strategies for various neurodegenerative diseases focus on inhibiting protein fibrillation, clearing aggregated protein plaques from the brain, and lowering protein-aggregate-induced toxicity. We have designed poly­(trehalose) nanoparticles that can inhibit amyloid/polyglutamine aggregation under extra-/intracellular conditions, reduce such aggregation-derived cytotoxicity, and prevent polyglutamine aggregation in a Huntington’s disease (HD) model mouse brain. The nanoparticles have a hydrodynamic size of 20–30 nm and are composed of a 6 nm iron oxide core and a zwitterionic polymer shell containing ∼5–12 wt % covalently linked trehalose. The designed poly­(trehalose) nanoparticles are 1000–10000 times more efficient than molecular trehalose in inhibiting protein fibrillation in extra-cellular space, in blocking aggregation of polyglutamine-containing mutant huntingtin protein in model neuronal cells, and in suppressing mutant huntingtin aggregates in HD mouse brain. We show that the nanoparticle form of trehalose with zwitterionic surface charge and a trehalose multivalency (i.e., number of trehalose molecules per nanoparticle) of ∼80–200 are crucial for efficient brain targeting, entry into neuronal cells, and suppression of mutant huntingtin aggregation. The present work shows that nanoscale trehalose can offer highly efficient antiamyloidogenic performance at micromolar concentration, compared with millimollar to molar concentrations for molecular trehalose. This approach can be extended to in vivo application to combat protein-aggregation-derived neurodegenerative diseases.