Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance,neuroinflammation and Alzheimer’s disease  

作　　者：Alessandro Dario Confettura Eleonora Cuboni Mohamed Rafeet Ammar Shaobo Jia Guilherme M.Gomes PingAn Yuanxiang Rajeev Raman Tingting Li Katarzyna M.Grochowska Robert Ahrends Anna Karpova Alexander Dityatev Michael R.Kreutz 

机构地区：[1]RG Neuroplasticity,Leibniz-Institute for Neurobiology,39118 Magde-burg,Germany [2]German Center for Neurodegenerative Diseases(DZNE),39120 Magdeburg,Germany [3]Center for Behavioral Brain Sciences,Otto Von Guericke University,39120 Magdeburg,Germany [4]Leibniz-Institut Für Analytische Wissenschaften-ISAS-e.V.,44227 Dortmund,Germany [5]Leibniz Group‘Dendritic Organelles and Synaptic Function’,Center for Molecular Neurobiology,ZMNH,University Medical Center Hamburg-Eppendorf,20251 Ham-burg,Germany [6]Department of Analytical Chemistry,Faculty of Chemistry,University of Vienna,1090 Wien,Austria [7]Medical Faculty,Otto-von-Guericke University,39120 Magdeburg,Germany.

出　　处：《Translational Neurodegeneration》2022年第1期931-948,共18页转化神经变性病（英文）

基　　金：the Deutsche Forschungsgemeinschaft(DFG)(Kr 1879/9-1/FOR 2419,Kr1879/5-1/6-1/10-1;CRC1436 A02 Project-ID 425899996;Research Training Group 2413 SynAGE,TP4),BMBF‘Energi’FKZ:01GQ1421B,The EU Joint Programme-Neurodegenerative Disease Research(JPND)project STAD(01ED1613)and Leibniz Foundation SAW‘ISAS2’,’SynMetAge’,’Neurotranslation’and’SynErca’to MRK.;CRC1436 A02 Project-ID 425899996 to AK;CRC1436 A05 Project-ID 425899996,Research Training Group 2413 SynAGE TP5 and BMBF‘Energi’FKZ:01GQ1421A to AD.G.M.G.was supported by the Alexander-von-Humboldt Foundation/CAPES post-doctoral research fellowship(99999.001756/2014-01).

摘　　要：Background:The metabolic syndrome is a consequence of modern lifestyle that causes synaptic insulin resistance and cognitive deficits and that in interaction with a high amyloid load is an important risk factor for Alzheimer’s dis-ease.It has been proposed that neuroinflammation might be an intervening variable,but the underlying mechanisms are currently unknown.Methods:We utilized primary neurons to induce synaptic insulin resistance as well as a mouse model of high-risk aging that includes a high amyloid load,neuroinflammation,and diet-induced obesity to test hypotheses on underly-ing mechanisms.Results:We found that neddylation and subsequent activation of cullin-RING ligase complexes induced synaptic insulin resistance through ubiquitylation and degradation of the insulin-receptor substrate IRS1 that organizes synap-tic insulin signaling.Accordingly,inhibition of neddylation preserved synaptic insulin signaling and rescued memory deficits in mice with a high amyloid load,which were fed with a’western diet’.Conclusions:Collectively,the data suggest that neddylation and degradation of the insulin-receptor substrate is a nodal point that links high amyloid load,neuroinflammation,and synaptic insulin resistance to cognitive decline and impaired synaptic plasticity in high-risk aging.

关 键 词：Metabolic syndrome Alzheimer’s disease NEDDYLATION Cullins MLN-4924 Insulin IRS1 Amyloid-β TNFα 

分 类 号：R749.16[医药卫生—神经病学与精神病学]