Attenuation of Tau-Mediated β-Amyloid1-42 Aggregation by Native PLGA Nanoparticles and Its Relevance to Alzheimer Disease Pathology

Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by the presence of extracellular β-amyloid (Aβ)-containing neuritic plaques, intracellular tau-positive neurofibrillary tangles and loss of selected neurons in the brain. Evidence suggests that aggregation of Aβ and tau via synergistic interactions initiates a cascade of events, leading to development of AD pathology. Thus, many studies are being pursued to develop small molecules/drugs that can target both Aβ and tau as an effective AD treatment strategy. In this study, we evaluated effects of native PLGA nanoparticles on tau-mediated Aβ1-42 aggregation using biophysical, structural, spectroscopic and biochemical approaches. Our results show that 0N4R tau seeds enhanced Aβ1-42 aggregation, and that this effect is mitigated by native PLGA. Additionally, PLGA inhibited Aβ1-42 aggregation induced by both 0N4R and 2N4R tau isoforms. The presence of PLGA during the formation of tau seeds or pretreatment of tau seeds with PLGA attenuates subsequent Aβ1-42 aggregation. Interestingly, monomeric 0N4R tau, unlike 0N4R tau seeds, suppressed Aβ1-42 aggregation, which is diminished further by PLGA nanoparticles. However, we have not addressed the implications of native PLGA on tau/Aβ1-42 interaction using any cellular or animal models of AD. Nevertheless, our results reveal that tau seeds and monomeric tau can differentially influence Aβ1-42 aggregation, which is mitigated by native PLGA under in vitro conditions, providing a rationale to study it further under an in vivo paradigm to examine its significance in AD pathogenesis.