Anti-diabetic vanadyl complexes reduced Alzheimer's disease pathology independent of amyloid plaque deposition  

作　　者：Yaqiong Dong TessANDra Stewart Yue Zhang Min Shi Chang Tan Xue Li Lan Yuan Aanchal Mehrotra Jing Zhang Xiaoda Yang 

机构地区：[1]The State Key Laboratories of Natural and Biomimetic Drugs and Department of Chemical Biology, School of Pharmaceutical Sciences,Peking University Health Science Center [2]Department of Pathology, University of Washington School of Medicine [3]Department of Pathology, School of Basic Medical Sciences and Peking University Third Hospital, Peking University Health Science Center

出　　处：《Science China(Life Sciences)》2019年第1期126-139,共14页中国科学（生命科学英文版）

基　　金：supported by National Natural Science Foundation of China (21571006, 21771010);Beijing Municipal Science & Technology Commission (A61120-01);the "Strategic Priority Research Program" of the Chinese Academy of Sciences (XDA 12040101)

摘　　要：Association of Alzheimer's disease(AD) with cerebral glucose hypometabolism, likely due to impairments of insulin signaling,has been reported recently, with encouraging results when additional insulin is provided to AD patients. Here, we tested the potential effects of the anti-diabetic vanadium, vanadyl(IV) acetylacetonate(VAC), on AD in vitro and in vivo models. The experimental results showed that VAC at sub-micromolar concentrations improved the viability of neural cells with or without increased β-amyloid(Aβ) burden; and in APP/PS1 transgenic mice, VAC treatment(0.1 mmol kg-1 d-1) preserved cognitive function and attenuated neuron loss, but did not reduce brain Aβ plaques. Further studies revealed that VAC attenuated Aβpathogenesis by(i) activation of the PPARγ-AMPK signal transduction pathway, leading to improved glucose and energy metabolism;(ii) up-regulation of the expression of glucose-regulated protein 75(Grp75), thus suppressing p53-mediated neuronal apoptosis under Aβ-related stresses; and(iii) decreasing toxic soluble Aβ peptides. Overall, our work suggested that vanadyl complexes may have great potential for effective therapeutic treatment of AD.Association of Alzheimer's disease(AD) with cerebral glucose hypometabolism, likely due to impairments of insulin signaling,has been reported recently, with encouraging results when additional insulin is provided to AD patients. Here, we tested the potential effects of the anti-diabetic vanadium, vanadyl(IV) acetylacetonate(VAC), on AD in vitro and in vivo models. The experimental results showed that VAC at sub-micromolar concentrations improved the viability of neural cells with or without increased β-amyloid(Aβ) burden; and in APP/PS1 transgenic mice, VAC treatment(0.1 mmol kg-1 d-1) preserved cognitive function and attenuated neuron loss, but did not reduce brain Aβ plaques. Further studies revealed that VAC attenuated Aβpathogenesis by(i) activation of the PPARγ-AMPK signal transduction pathway, leading to improved glucose and energy metabolism;(ii) up-regulation of the expression of glucose-regulated protein 75(Grp75), thus suppressing p53-mediated neuronal apoptosis under Aβ-related stresses; and(iii) decreasing toxic soluble Aβ peptides. Overall, our work suggested that vanadyl complexes may have great potential for effective therapeutic treatment of AD.

关 键 词：Alzheimer's disease vanadyl(IV) acetylacetonate NEUROPROTECTION Aβ oligomerization PPARγ-AMPK GRP75 

分 类 号：Q[生物学]