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Temperature-dependent aggregation of tau protein is attenuated by native PLGA nanoparticles under in vitro conditions

From National Research Council Canada

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DOIResolve DOI: https://doi.org/10.2147/IJN.S494104
AuthorSearch for: ; Search for: ; Search for: 1; Search for: ; Search for: ; Search for: ; Search for: 1ORCID identifier: https://orcid.org/0000-0002-1868-6464; Search for: ORCID identifier: https://orcid.org/0000-0001-5102-8706; Search for: ; Search for: ; Search for: ORCID identifier: https://orcid.org/0000-0003-0167-3808
Affiliation
  1. National Research Council Canada. Quantum and Nanotechnologies
FormatText, Article
Subjecttau protein; PLGA nanoparticles; au pathology; protein aggregation
Abstract
Introduction: Hyperphosphorylation and aggregation of the microtubule-associated tau protein, which plays a critical role in many neurodegenerative diseases (ie, tauopathies) including Alzheimer’s disease (AD), are known to be regulated by a variety of environmental factors including temperature. In this study we evaluated the effects of FDA-approved poly (D,L-lactide-co-glycolic) acid (PLGA) nanoparticles, which can inhibit amyloid-β aggregation/toxicity in cellular/animal models of AD, on temperature-dependent aggregation of 0N4R tau isoforms in vitro. Methods: We have used a variety of biophysical (Thioflavin T kinetics, dynamic light scattering and asymmetric-flow field-flow fractionation), structural (fluorescence imaging and transmission electron microscopy) and biochemical (Filter-trap assay and detection of soluble protein) approaches, to evaluate the effects of native PLGA nanoparticles on the temperature-dependent tau aggregation. Results: Our results show that the aggregation propensity of 0N4R tau increases significantly in a dose-dependent manner with a rise in temperature from 27°C to 40°C, as measured by lag time and aggregation rate. Additionally, the aggregation of 2N4R tau increases in a dose-dependent manner. Native PLGA significantly inhibits tau aggregation at all temperatures in a concentration-dependent manner, possibly by interacting with the aggregation-prone hydrophobic hexapeptide motifs of tau. Additionally, native PLGA is able to trigger disassembly of preformed 0N4R tau aggregates as a function of temperature from 27°C to 40°C. Conclusion: These results, taken together, suggest that native PLGA nanoparticles can not only attenuate temperature-dependent tau aggregation but also promote disassembly of preformed aggregates, which increased with a rise of temperature. Given the evidence that temperature can influence tau pathology, we believe that native PLGA may have a unique potential to regulate tau abnormalities associated with AD-related pathology.
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PublisherDovepress
Taylor & Francis Group
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  • International Journal of Nanomedicine 20 (14 February 2025): 1999–2019.
LanguageEnglish
Peer reviewedYes
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Record identifier145f619c-eb51-4561-b788-3206b3a6162a
Record created2025-06-09
Record modified2025-06-09
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