Significance of native PLGA nanoparticles in the treatment of Alzheimer's disease pathology

Alzheimer's disease (AD) is believed to be triggered by increased levels/aggregation of beta-amyloid (A beta) peptides. At present, there is no effective disease-modifying treatment for AD. Here, we evaluated the therapeutic potential of FDA-approved native poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles on A beta aggregation and in cellular/animal models of AD. Our results showed that native PLGA can not only suppress the spontaneous aggregation but can also trigger disassembly of preformed A beta aggregates. Spectroscopic studies, molecular dynamics simulations and biochemical analyses revealed that PLGA, by interacting with the hydrophobic domain of A beta(1-42), prevents a conformational shift towards the beta-sheet structure, thus precluding the formation and/or triggering disassembly of A beta aggregates. PLGA-treated A beta samples can enhance neuronal viability by reducing phosphorylation of tau protein and its associated signaling mechanisms. Administration of PLGA can interact with A beta aggregates and attenuate memory deficits as well as A beta levels/deposits in the 5xFAD mouse model of AD. PLGA can also protect iPSC-derived neurons from AD patients against A beta toxicity by decreasing tau phosphorylation. These findings provide unambiguous evidence that native PLGA, by targeting different facets of the A beta axis, can have beneficial effects in mouse neurons/animal models as well as on iPSC-derived AD neurons - thus signifying its unique therapeutic potential in the treatment of AD pathology.