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

Abstract

Conversion of β-amyloid (Aβ) peptides from soluble random-coil to aggregated protein enriched with β-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 Aβ 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 Aβ axis. In this study, using biochemical, structural and spectroscopic analyses, we evaluated the effects of native PLGA on temperature-dependent Aβ aggregation and its ability to protect cultured neurons from degeneration. Our results show that the rate of spontaneous Aβ1–42 aggregation increases with a rise in temperature from 27 to 40 °C and PLGA with 50:50 resomer potently inhibits Aβ 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 Aβ1–42, prevents a conformational shift towards β-sheet structure, thus precluding the formation of Aβ aggregates. Additionally, PLGA triggers disassembly of matured Aβ1–42 fibers at a faster rate at 40 °C than at 27 °C. PLGA-treated Aβ samples can significantly enhance viability of cortical cultured neurons compared to neurons treated with Aβ alone by attenuating phosphorylation of tau protein. Injection of native PLGA is found to influence the breakdown/clearance of Aβ peptide in the brain. Collectively, these results suggest that PLGA nanoparticles can inhibit Aβ aggregation and trigger disassembly of Aβ aggregates at temperatures outside the physiological range and can protect neurons against Aβ-mediated toxicity thus validating its unique therapeutic potential in the treatment of AD pathology. Graphical Abstract

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

“…3 G). Consistent with earlier reports 29 , our results indicated that tau samples after 40 h incubation without heparin or Aβ seed demonstrated a random coil structure (random coil and others 91.1%, α-helix 2.6%, β-sheet 6.3%) with minima around 200 nm, indicating an absence of aggregate formation. In the presence of Aβ seed and heparin, tau exhibited a change in its conformation from a random coil to a predominant β-sheet structure (random coil and others 16%, α-helix 4.8%, β-sheet 79.2%) displaying minima around 216 nm with a faint shoulder peak at 222 nm.…”

“…Apart from functionalized PLGA, we recently reported that PLGA nanoparticles without any drug/agent (i.e. native PLGA) can suppress Aβ aggregation/toxicity in cellular and animal models of AD 27 – 29 . However, no information is currently available if native PLGA can influence the aggregation, seeding or spreading of tau protein that acts synergistically with Aβ to trigger AD pathogenesis.…”

Extracellular vesicles enriched with amylin receptor are cytoprotective against the Aß toxicity in vitro

“…The data were collected without attenuation and a minimum number of 10 consecutive runs of 10sec each was averaged to obtain the autocorrelation function. Particle size was calculated by the manufacturer’s software through the Stokes–Einstein equation assuming spherical shapes of the particles [ 22 ].…”

Alzheimer's Disease: Status of Low‐Dimensional Nanotherapeutic Materials

“…[ 273 ] Even with the temperature rising from 37 °C to 40 °C, the unconjugated PLGA nanoparticles still remain the ability to dissociate Aβ1‐42 aggregation. [ 274 ] Although the formation of PEG layers improves the stability of the delivered drug, the layers would reduce the drug encapsulation rate. Therefore, in response to this concern and the excellent curative effect of PLGAs, many studies have begun to encapsulate therapeutic AD drugs into PLGAs with organic or inorganic materials which have achieved rather considerable success in therapy recently.…”