Design And Synthesis Of Novel Multifunctional Aβ Inhibitors And Their Applications In Alzheimer’s Disease Model

Alzheimer’s disease(AD),a progressive,irreversible and devastating neurodegenerative disorder,affects approximately 50 million people globally.Substantial evidences have revealed that accumulation and aggregation of amyloid-β(Aβ)peptide in the brain are a central event of AD pathogenesis,which triggers a variety of other pathogenic processes such as oxidative stress,synaptic impairment,and neuronal loss.Therefore,Aβ has been considered as a potential therapeutic target for AD.Inorganic nanomaterials hold tremendous potential in the treatment of AD because of their multifunctional properties,adjustable structures,and excellent physicochemical stability.Herein,we design and synthesize a series of inorganic nanoparticles for reduction of Aβ burden and mitigation of Aβ-induced neurotoxicity.The main results are summarized as follows:1.In combination of the advantages of two-dimensional molybdenum disulfide nanosheets and the cobalt complex,we rationally construct a near-infrared(NIR)-controllable artificial enzyme(MoS2-Co)that circumvents the β-sheet structures restrictions by simultaneous inhibition of Aβ aggregation and disaggregation of Aβ fibrils.Consequently,MoS2-Co can increase the hydrolytic activity towards Aβ peptides,resulting in mitigating the attendant cytotoxicity.In addition,the well-designed MoS2-Co is easy to graft Aβ recognition agent,which can avoid misdirected or undesired hydrolysis reactions.This approach may be adapted for hydrolysis of other types of amyloids.2.We construct an Aβ targeting,N-doped three-dimensional mesoporous carbon nanosphere(KD8@N-MCNs)with excellent second near-infrared(NIR-II)photothermal performances and dual enzyme-like activities(i.e.,superoxide dismutase and catalase).Based on this,KD8@N-MCNs disassembles Aβ42 aggregates through skull and scalp as well as eliminates intracellular superfluous reactive oxygen species(ROS).Besides,KD8@N-MCNs traverses the blood-brain barrier efficiently.As a consequence,KD8@N-MCNs can reduce Aβ deposits and alleviate neuroinflammation in 3xTg-AD mice.3.A NIR regulated surface-transformable and target peptide-guided upconversion nanoplatform(UCNP/ONA-P/K)is constructed.Taking advantage of preeminent biocompatibility,high selectivity toward Aβ,and surface-transformable property,the UCNP/ONA-P/K can achieve enhanced Aβ enrichment and clearance by a combination of prolonging blood circulation,preventing the unfavorable aggregation of Aβ,and synchronously facilitating the hepatic uptake of the captured Aβ peptides.After verified by a series of in vitro blood Aβ clearance,systematic toxicity evaluation,cell uptake,deep tissue penetration,and hemolytic experiments,in vivo studies demonstrate that UCNP/ONA-P/K decreases brain Aβ burden and reverses memory deficits in commonly used 3xTg-AD mouse model.4.A biomimetic nanozyme(CuxO@EM-K)with improved protein adsorption resistance,enhanced biocompatibility and minimized immunogenicity is designed and synthesized,which is composed of CuxO nanoparticle wrapped with modified erythrocyte membrane with Aβ recognition element KLVFF.KLVFF works together with erythrocyte membrane to selectively capture Aβ in the blood.Concurrently,the erythrocyte membrane coating prevents the formation of protein corona and hence preserves the Aβ-targeting ability of CuxO@EM-K in the blood.More importantly,the inner CuxO with multiple antioxidant enzyme-like activities alleviates Aβ-mediated erythrocyte membrane oxidative injury and stabilizes the outer membrane.In vivo experiments show that CuxO@EM-K not only decreases Aβlevels in both the blood and the brain,but also improves spatial memory impairments in commonly used 3xTg-AD mouse model.Furthermore,CuxO@EM-K has no noticeable toxicity in 3xTg-AD mice.