Unconjugated PLGA nanoparticles attenuate temperature-dependent ß-amyloid aggregation and protect neurons against toxicity: implications for Alzheimer's disease pathology.

Conversion of ß-amyloid (Aß) peptides from soluble random-coil to aggregated protein enriched with ß-sheet-rich intermediates has been suggested to play a role in the degeneration of neurons and development of Alzheimer's disease (AD) pathology. Aggregation of Aß peptide can be prompted by a variety of environmental factors including temperature which can influence disease pathogenesis. Recently, we reported that FDA-approved unconjugated poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles can have beneficial effects in cellular and animal models of AD by targeting different facets of the Aß axis. In this study, using biochemical, structural and spectroscopic analyses, we evaluated the effects of native PLGA on temperature-dependent Aß aggregation and its ability to protect cultured neurons from degeneration. Our results show that the rate of spontaneous Aß1-42 aggregation increases with a rise in temperature from 27 to 40 °C and PLGA with 50:50 resomer potently inhibits Aß aggregation at all temperatures, but the effect is more profound at 27 °C than at 40 °C. It appears that native PLGA, by interacting with the hydrophobic domain of Aß1-42, prevents a conformational shift towards ß-sheet structure, thus precluding the formation of Aß aggregates. Additionally, PLGA triggers disassembly of matured Aß1-42 fibers at a faster rate at 40 °C than at 27 °C. PLGA-treated Aß samples can significantly enhance viability of cortical cultured neurons compared to neurons treated with Aß alone by attenuating phosphorylation of tau protein. Injection of native PLGA is found to influence the breakdown/clearance of Aß peptide in the brain. Collectively, these results suggest that PLGA nanoparticles can inhibit Aß aggregation and trigger disassembly of Aß aggregates at temperatures outside the physiological range and can protect neurons against Aß-mediated toxicity thus validating its unique therapeutic potential in the treatment of AD pathology.

Native PLGA nanoparticles attenuate Aß-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer's disease pathology.

Evidence suggests that beta-amyloid (Aß)-induced phosphorylation/aggregation of tau protein plays a critical role in the degeneration of neurons and development of Alzheimer's disease (AD), the most common cause of dementia affecting the elderly population. Many studies have pursued a variety of small molecules, including nanoparticles conjugated with drugs to interfere with Aß and/or tau aggregation/toxicity as an effective strategy for AD treatment. We reported earlier that FDA approved PLGA nanoparticles without any drug can attenuate Aß aggregation/toxicity in cellular/animal models of AD. In this study, we evaluated the effects of native PLGA on Aß seed-induced aggregation of tau protein using a variety of biophysical, structural and spectroscopic approaches. Our results show that Aß1-42 seeds enhanced aggregation of tau protein in the presence and absence of heparin and the effect was attenuated by native PLGA nanoparticles. Interestingly, PLGA inhibited aggregation of both 4R and 3R tau isoforms involved in the formation of neurofibrillary tangles in AD brains. Furthermore, Aß seed-induced tau aggregation in the presence of arachidonic acid was suppressed by native PLGA. Collectively, our results suggest that native PLGA nanoparticles can inhibit the Aß seed-induced aggregation of different tau protein isoforms highlighting their therapeutic implication in the treatment of AD.