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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. JanaPrevention
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.
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protein fibrillationnanoparticlezwitterionic surface chargeSuppress Polyglutamine Aggregationneurodegenerative diseases focusHD mouse brainaggregated protein plaquesmodel mouse brain6 nm iron oxide coretrehalosezwitterionic polymer shellcombat protein-aggregation-derived neurodegenerative diseaseshuntingtin
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