Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathology  

作　　者：Hoda M.Gebril Aravind Aryasomayajula Mariana Reis Nogueira de Lima Kathryn E.Uhrich Prabhas V.Moghe 

机构地区：[1]Department of Biomedical Engineering,Rutgers University,599 Taylor Rd.,Piscataway,NJ 08854,USA [2]Department of Chemical and Biochemical Engi-neering,Rutgers University,98 Brett Rd.,Piscataway,NJ 08854,USA [3]Department of Chemistry,University of California,501 Big Springs Rd.,Riverside,CA 92507,USA

出　　处：《Translational Neurodegeneration》2024年第1期1083-1106,共24页转化神经变性病(英文)

基　　金：funded by NIH-NIA R21AG060024 and Rutgers University。

摘　　要：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(Aβ)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 Aβ(fAβ)burden,microglial modulation,and neuroprotection.Methods We designed a nanotechnology approach to regulate the SR-mediated intracellular fAβtrafficking 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 Aβfibrilization,fAβ-mediated microglial inflammation,and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines.Results AM-NPs interrupted Aβfibrilization,attenuated fAβmicroglial internalization via targeting the fAβ-specific SRs,arrested the fAβ-mediated microglial activation and pro-inflammatory response,and accelerated lysosomal degradation of intracellular fAβ.Moreover,AM-NPs counteracted the microglial-mediated neurotoxicity after exposure to fAβ.Conclusions The AM-NP nanotechnology presents a multifactorial strategy to target pathological Aβaggregation and arrest the fAβ-mediated pathological progression in microglia and neurons.

关 键 词：Amphiphilic nanoparticle MICROGLIA Fibril amyloid beta Alzheimer’s disease NEUROINFLAMMATION Scavenger receptor 

分 类 号：R749.16[医药卫生—神经病学与精神病学]