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

Abstract

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.

Zwitterionic Polymer Design that Inhibits Aggregation and Facilitates Insulin Refolding: Mechanistic Insights and Importance of Hydrophobicity

“…Transmission electron microscopy (TEM) reveals that hydrophobic poly‐SPB shows self‐assembly (Figure S19, Supporting Information), which may be related to the high aggregation inhibition behavior. Previous studies also indicate that self‐assembled polymers nanogels and polymer coated metallic nanoparticles show significantly higher efficiency than its linear counterparts.…”

Recent Progress of Nanomedicine in the Treatment of Central Nervous System Diseases

“…Debnath et al. designed poly(trehalose) NPs that inhibited amyloid/polyglutamine aggregation under extra‐/intracellular conditions, reduced such aggregation‐derived cytotoxicity, and prevented polyglutamine aggregation in a HD model mouse brain …”

The Role of Natural Compounds and their Nanocarriers in the Treatment of CNS Inflammation

“…Thus, when using this ligand as targeting moieties with BBB-targeting ligands, such as T7 peptide or angiopep-2, the NPs loaded with natural compounds can be neutrophil-targeting systems toward the neuroinflammatory sites in the brain [ 241 , 242 ]. In the same way, trehalose ligands, which are multi-covalently linked to NPs, can specifically interact with intracellular huntingtin proteins in an HD-induced brain [ 243 ]. The Tet-1 peptide ligand can specifically interact with neurons, thereby localizing loaded natural compounds into the neuronal cells and enhancing their therapeutic efficacies [ 244 ].…”