The Synthesis Of Multifunctional Selenium Nanoparticle And Its Potential Use As An Inhibitor Of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia and a growingconcern in the modern world. Nowadays the number of individuals affected with ADis increasing exponentially. Therefore, strategies for the AD therapy are among one ofthe most challenging and timely areas of study in modern medicine. AD pathologyincludes amyloid plaques accumulation, tau protein hyperphosphorylation, oxidativestress, and cell apoptosis in the brain of patient. However, the molecular mechanismsof AD pathogenesis are not fully understood. Recent studies have demonstrated thatamyloid-β (Aβ) polymerization may be crucial to AD pathologies. Therefore, therehas been a considerable effort to develop new drugs, which can inhibit Aβ fibrillation.Functionalized nano-seleniums (SeNPs) have recently become one of the hotresearch fields of nanomaterials owing to its high bioavailability, low toxicity, andextensive anti-tumor activity. However, the interaction between SeNPs and Aβaccosiated with AD has rarely been studied. Because many SeNPs can inhibit cancercells apoptosis, and the nature of AD symptoms is also about the apoptosis andnecrosis of neurons, this study attempts to synthesize a series of functionalized SeNPsto study the interaction between SeNPs and Aβ. Based on the above background andthe work of pioneer contributors, we prepared three groups of functionalized SeNPs inthe aqueous phase to study their interactions with Aβ accosiated with AD aiming tofind a potential targeted nanomedicine for the treatment of AD. Four chaptersconstitute this thesis.In chapter1, we firstly describe the pathogenesis and characteristic pathologicalchanges of AD, and then focus on the present nano research methods and progress inthe treatment of AD. Finally, we point out the challenges and difficulties of the currenttreatment of AD and give the purpose and significance of this thesis.In chapter2, EGCG-stabilized SeNPs (EGCG@Se) were firstly synthesizedfollowed by the coating of Tet-1peptide on EGCG@Se (Tet-1-EGCG@Se). Westudied the interactions between the two SeNPs and Aβ, and the results showed that Tet-1-EGCG@Se was capable of binding Aβ fibrils with high affinity, inhibiting Aβaggregation, and disaggregating Aβ fibrils. Cell experiments revealed thatTet-1-EGCG@Se could target and be well absorbed by PC12cells, which led to theinhibition of intracellular Aβ aggregation and reduced cytotoxicity induced by Aβ.In chapter3, we firstly the synthesized and characterized two kinds ofpolyoxometalate-modified selenium nanoparticles (PTA@Se and PMA@Se), andthen studied the interactions between PTA@Se (or PMA@Se) and Aβ by fluorescencespectroscopy, circular dichroism (CD), transmission electron microscopy (TEM),atomic force microscopy (AFM) and other methods. The results showed that bothtPTA@Se and PMA@Se can be good inhibitors of Aβ aggregation. Meanwhile,PTA@Se and PMA@Se turned out to be able to protect PC12cells against synapsedamage and cytotoxicity induced by Aβ.In the fourth chapter, we conjugated sialic acid and brain vascular endothelialcells targeting peptide (B6peptide) to the nano-selenium to study the role ofnanoparticles penetrating the vascular endothelial cells its neuroprotective effect.Firstly, we studied the interaction between nanoparticles and Aβ in vitro, and then wesimulated BBB (Blood Brain Barrier) model to investigate the efficiency ofnanoparticles crossing the brain endothelial cells. The results showed that thisnanoparticle was not only a potential inhibitor of Aβ aggregation, but also a possiblenew nano-medicine capable of crossing BBB.