Design Of Multifunctional Molecules For The Treatment Of Alzheimer’s Disease

Alzheimer’s disease is a very serious neurodegenerative disease,which brings huge financial burden and mental suffering to the families of patients.Amyloid cascade hypothesis is the most prevalent theory about Alzheimer’s disease.The hypothesis suggests that Aβ aggregation plays play an important role in the process of Alzheimer’s disease,but drug development based on this hypothesis has failedAβ protein may play an important role in the initial stage of AD,and downstream pathological processes,such as neuroinflammation,aggravate its detrimental effects Relevant studies have shown that Aβ aggregates can act on immune cells in the brain and activate innate immune responses.It is thought that immune system-mediated neuroinflammation may have an important effect on the pathogenesis of AD.Soluble Aβ oligomers and Aβfibers can activate NLRP3 inflammasome in microglia which releases inflammatory factors such as IL-1βand IL-18.Therefore,compounds that can inhibit Aβ aggregates and NLRP3 inflammasome have become important drug candidates.Based on amyloid cascade hypothesis and NLRP3 inflammasome,a multifunctional molecule HBM was designed and synthesized.Fluorescence spectra showed that HBM could bind to Aβ aggregates.UV and fluorescence spectra showed that HBM could bind to Cu2+ and Zn2+ effectively.THT fluorescence、ANS fluorescence、TEM experiments found that HBM can inhibit the self-aggregation of Atβ,the aggregation induced by Cu2+ or Zn2+,and disaggregate the formed Afi aggregates.HBM can also effectively delay the paralysis of CL4176 nematode.Western blot and ELISA results showed that HBM inhibited the activation of inflammasome in macrophagesFurther experiments on AD mice showed that HBM could improve the cognitive and memory abilities of AD mice,and reduce the levels of Aβ aggregates and IL-1β in the brain of AD mice.All in all,multifunctional molecule HBM was designed and synthesized which can reduce the toxicity of Aβ aggregates and inhibit the activation of NLRP3 inflammasome by Aft aggregates,thus realizing multi-targeted therapy for Alzheimer’s disease.