Design And Synthesis Of Multifunctional Molecular Probes For The Diagnosis And Applications In Alzheimer’s Disease

Alzheimer’s disease(AD)is the leading and common dementia and it is rapidly becoming one of the most expensive,deadly and burdensome diseases.However,the pathogenesis of AD has not been fully elucidated,leading to no effective drugs being able to reverse the progression of AD.So far,various hypotheses for the pathogenesis of AD have been put forward by researchers,includingβ-amyloid(Aβ)cascade hypothesis,Tau hypothesis,and oxidative stress hypothesis.At present,the diagnosis and treatment of AD are mostly concentrated on the two pathological proteins Aβand Tau.In addition,many studies have shown that AD patients have excess reactive oxygen species(ROS)in the brain compared to normal people.It is quite important for the detection of pathological proteins and ROS.Compared to other techniques,fluorescent imaging possesses many advantages,such as low cost,simple operation and stable structure,which is widely used in the diagnosis and treatment of AD.This dissertation is focused on the following research work:It is well known that the content of Aβfibrils in the brains of AD patients is significantly higher than that of normal persons.However,it is still quite difficult to sensitively detect Aβfibrils in brain tissues or in vivo due to the limited sensitivity of probe.Therefore,in the first work of this dissertation,a fluorescent probe KZ containing zinc ions was synthesized for the specific and sensitive detection of Aβfibrils.The probe KZ could detect Aβfibrils with high sensitivity and selectivity in vitro.Furthermore,KZ exhibited excellent anti-interference ability and stability even in the presence of some reactive oxygen/nitrogen species,anions,amino acids,reducing substances(glutathione and glucose)or over a wide p H range.Importantly,the probe KZ could recognize Aβfibrils in brain slices from AD transgenic mouse models.This work may pave the way for the development of fluorescent probes to sensitively detect AD pathological proteins.However,increasing evidence unveiled that Tau protein has a stronger correlation with AD pathogenesis.Studies have shown that the aggregation of Tau protein can lead to nerve cell death,and the aggregated Tau protein can spread across cells,inducing more nerve cell death.Based on this,we designed and synthesized a multifunctional probe MB-WK-NA for inhibiting the aggregation of Tau protein and its spread across cells.MB-WK-NA could selectively respond to hypochlorous acid(HOCl)in vitro to release the Tau protein aggregation inhibitor methylene blue(MB).In addition,MB-WK-NA showed excellent Tau targeting ability in cells.Importantly,the probe MB-WK-NA could inhibit Tau aggregation and cross cell transmission of aggregated Tau in cells.The development of this work will provide a theoretical basis for in-depth understanding of the correlation between Tau protein and AD.In addition,HOCl,one of the common ROS,plays a non-negligible role in the pathogenesis of AD.A number of fluorescent probes have been developed by researchers for the detection of HOCl.However,these fluorescent probes inevitably have shortcomings including weak fluorescence penetration through tissue or low spatial resolution.Proton magnetic resonance spectroscopy(~1H-MRS)is a non-invasive technique for detecting metabolic changes in the human body,with the advantages of high magnetic sensitivity and strong signal.Therefore,we designed and synthesized a proton magnetic resonance spectroscopy probe SF for the specific detection of HOCl.The probe SF reacted specifically with HOCl to show a 9.75 chemical shift on the magnetic resonance spectrum,which has possibility of being further applied to in vivo magnetic resonance spectroscopy imaging.