Abstract
Background Alzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (A[beta]) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril A[beta] (fA[beta]) burden, microglial modulation, and neuroprotection. Methods We designed a nanotechnology approach to regulate the SR-mediated intracellular fA[beta] trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM-NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM-NPs on A[beta] fibrilization, fA[beta]-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines. Results AM-NPs interrupted A[beta] fibrilization, attenuated fA[beta] microglial internalization via targeting the fA[beta]-specific SRs, arrested the fA[beta]-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fA[beta]. Moreover, AM-NPs counteracted the microglial-mediated neurotoxicity after exposure to fA[beta]. Conclusions The AM-NP nanotechnology presents a multifactorial strategy to target pathological A[beta] aggregation and arrest the fA[beta]-mediated pathological progression in microglia and neurons.