Organoplatinum-substituted Polyoxometalate Inhibit A? Aggregation And Its Therapy Effect For AD Transgenic Mice

Alzheimer's disease?AD?is a global neurodegenerative disorder,and age is one of the most important risk factors.AD is characterized by impairment in cognitive function and the serious patients usually lose their ability to live independently.At present,AD has become one of the major problems faced by modern medicine,because it is difficult to treatment,and it can cause large social burden.There are only few drugs can be used in clinic for AD,including cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists.The limitation of these two kinds of drug is that they can only alleviate the symptoms,but cannot eradicate the disease.?-amyloid?A??is one of the major pathogenic hallmark of AD.Therefore,development of novel drugs inhibiting the formation of?-sheet and cleaving?-sheet could be an effective way for AD therapy.Polyoxometalates?POMs?can inhibit aggregation of A?.To improve its shortcoming,such as the higher toxicity,the poor stability and no targeting property,the organic groups with excellent molecular tailoring and modified functions into POMs matrix.Furthermore,to enhance anti-A?efficacy,coordinated with divalent platinum.In this study,a kind of the organoplatinum-substituted Keggin-type structure Polyoxometalates,?Me₄N?₃[PW₁₁O₄₀?Si C₃H₆NH₂?₂Pt Cl₂](Pt^II-PW₁₁)were synthesized.We studied the inhibition of Pt^II-PW₁₁for the aggregation of A?₄₂by thioflavin T?ThT?fluorescence assay and transmission electron microscope?TEM?.It indicated that the inhibiting efficiency of Pt^II-PW₁₁is dependent on the concentration in the range of 0?mol/L and 5?mol/L.The mechanism of inhibition was studied by circular dichroism?CD?,isothermal titration calorimetry?ITC?and relaxation time.On the one hand,Pt^II-PW₁₁can preferentially bind to A?₄₂through electrostatic interactions,hydrogen bonds,and Van der Waals forces to inhibit the formation of?-sheet.On the other hand,Pt²⁺in Pt^II-PW₁₁preferentially stabilizes the free-NH₃ in A?₄₂,to prevent the aggregation of A?₄₂.In vitro and in vivo experiments have shown that Pt^II-PW₁₁has low biological toxicity.Treating APP/PS1 transgenic mice with Pt^II-PW₁₁showed a significant therapeutic effect in the high-dose group?1.5 mg/m L?.The behavioral experiments showed that mice treated with Pt^II-PW₁₁improve their ability of learning and memory,and the pathological experiments indicated that Pt^II-PW₁₁could reduce the deposition of A?in the brain of AD mice.In summary,Pt^II-PW₁₁were synthesized,that is a novel anti-A?inhibitor with low toxicity and high efficiency.In vitro and in vivo experiments showed that Pt^II-PW₁₁can act as a candidate drug for AD therapy.