1. Temperature-Dependent Aggregation of Tau Protein Is Attenuated by Native PLGA Nanoparticles Under in vitro Conditions
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Paul PS, Rathnam M, Khalili A, Cortez LM, Srinivasan M, Planel E, Cho JY, Wille H, Sim VL, Mok SA, and Kar S
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tau protein ,plga nanoparticles ,tau pathology ,protein aggregation ,Medicine (General) ,R5-920 - Abstract
Pallabi Sil Paul,1 Mallesh Rathnam,1 Aria Khalili,2 Leonardo M Cortez,1 Mahalashmi Srinivasan,3 Emmanuel Planel,4 Jae-Young Cho,2,5 Holger Wille,3 Valerie L Sim,1 Sue-Ann Mok,3 Satyabrata Kar1 1Department of Medicine (Neurology), Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, T6G 2M8, Canada; 2Quantum and Nanotechnology Research Centre, National Research Council Canada, Edmonton, Alberta, Canada; 3Department of Biochemistry, Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada; 4Department of Psychiatry and Neurosciences, University of Laval, Quebec, Canada; 5Department of Mechanical Engineering, University of Alberta, Edmonton, Alberta, CanadaCorrespondence: Satyabrata Kar, Department of Medicine (Neurology), Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, T6G 2M8, Canada, Tel +1-780-492-9357, Fax +1-780-492-9352, Email skar@ualberta.caIntroduction: 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. Keywords: tau protein, PLGA nanoparticles, tau pathology, protein aggregation
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- 2025