Tau-targeted Multifunctional Nanocomposite Approach For Alzheimer's Disease Therapy

Alzheimer's disease(AD),a hidden onset,progressive neurodegenerative disease,remains an incurable disease and lacks efficient treatments.During the last 30 years,most AD treatments have focused on amyloid-?(A?)targeted therapy;however,the time has come to search for alternative theranostics due to accumulated findings of weak correlation between A? deposition and cognition,as well as the failures of Phase III clinical trials on Ap-targeted therapies.Recent studies have shown that the tau pathway is more closely associated with clinical symptoms of AD,which might be a potential therapeutic target.We herein use okadaic acid as an inductive tool for tau protein phosphorylation and construct a methylene blue(MB,a tau aggregation inhibitor)-loaded nanocomposite(CeNC/IONC/MSN-T807),which not only possesses high binding affinity to hyperphosphorylated tau,but also inhibits multiple key pathways of tau pathogenesis in AD development.We demonstrate that these nanocomposites can relieve the symptoms of AD by mitigating mitochondrial oxidative stress,suppressing tau hyperphosphorylation,and preventing neuronal death both in vitro and in vivo.The memory deficits of AD rats are significantly rescued upon treatment with MB-loaded CeNC/IONC/MSN-T807.Our results indicate that hyperphosphorylated tau-targeted multifunctional nanocomposites could be a promising therapeutic candidate for Alzheimer's disease.The main contents and conclusions of this dissertation are as follows:Part 1:To the best of our knowledge,this is hitherto the first study to construct a novel hyperphosphorylated tau-targeted multifunctional nanocomposite by controlled assembly of ultra-small ceria nanocrystals(CeNCs)and iron oxide nanocrystals(IONCs)onto the surface of mesoporous silica nanoparticles(MSNs).Amino-T807,an amino substituent of T807,was grafted onto the surface of MSNs,for active targeting of hyperphosphorylated tau.Furthermore,methylene blue(MB),a small molecular compound that can inhibit tau aggregation,was incorporated into the pores of MSNs.The resultant multifunctional nanocomposite CeNC/IONC/MSN-T807-MB,which exhibits good dispersion and stability,is expected to target phosphorylated tau and represent as an effective tau-targeted theranostic agent for AD treatment.Part 2:In this part,the characteristics of CeNC/IONC/MSN-T807-MB were tested in vitro.It was confirmed to be a tau-targeting,anti-oxidative nanocomposite that could inhibit tau phosphorylation and phosphorylated tau aggregation.The levels of p-Akt and p9-GSK3? were significantly increased in the group treated with CeNC/IONC/MSN-T807-MB,indicating the synergistic effect was elicited by Akt/GSK-3? pathway activation.Further,CeNC/IONC/MSN-T807-MB treatment significantly decreased both Bax and cleaved caspase-3 levels,suggesting that CeNC/IONC/MSN-T807-MB can suppress the pro-apoptotic pathway by scavenging ROS and maintaining the integrity of mitochondrial function.Taken together,CeNC/IONC/MSNT807-MB rescued neuronal cells from apoptosis by alleviating the ROS level and regulating pro-apoptotic proteins.Part 3:In this part of the study,the characteristics of CeNC/IONC/MSN-T807-MB were assessed in vivo.It has been demonstrated that NOTA could be labeled with 68Ga for PET imaging and IONCs were applicable for high-resolution magnetic resonance imaging(MRI),CeNC/IONC/MSN-T807-MB turned out to be an agent for dual-model imaging.Further,CeNC/IONC/MSN-T807-MB was corroborated to ameliorate learning and memory impairments and attenuate microgliosis in AD rat models.Eventually,it could be degraded in a physiological environment.It is expected to provide new ideas for tau targeted AD therapy.