Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model  

作　　者：Carolyn Tallon Benjamin J.Bell Medhinee M.Malvankar Pragney Deme Carlos Nogueras-Ortiz Erden Eren Ajit G.Thomas Kristen R.Hollinger Arindom Pal Maja Mustapic Meixiang Huang Kaleem Coleman Tawnjerae R.Joe Rana Rais Norman J.Haughey Dimitrios Kapogiannis Barbara S.Slusher 

机构地区：[1]Johns Hopkins Drug Discovery,Johns Hopkins University School of Medicine,Baltimore,MD 21205,USA [2]Neurology,Johns Hopkins University School of Medicine,Baltimore,MD 21205,USA [3]Cell Biology,Johns Hopkins University School of Medicine,Baltimore,MD 21205,USA [4]Oncology,Johns Hopkins University School of Medicine,Baltimore,MD 21205,USA [5]Medicine,Johns Hopkins University School of Medicine,Baltimore,MD 21205,USA [6]Pharmacology and Molecular Sciences,Johns Hopkins University School of Medicine,Baltimore,MD 21205,USA [7]Psychiatry and Behavioral Science,Johns Hopkins University School of Medicine,855 N.Wolfe Street,Rangos 278,Baltimore,MD 21205,USA [8]Intramural Research Program,Laboratory of Clinical Investigation,National Institute on Aging,National Institutes of Health,251 Bayview Blvd,Ste 8C228,Baltimore,MD 21224,USA [9]Johns Hopkins University School of Medicine,600 N.Wolfe Street,Pathology 517,Baltimore,MD 21287,USA

出　　处：《Translational Neurodegeneration》2023年第1期70-89,共20页转化神经变性病（英文）

基　　金：supported by the National Institute of Health Grants R01 AG059799(to BSS),R01AG057420 and R01MH131219(to NJH),P30 MH075673(to NJH and BSS);a grant from the Tau Consortium and Alzheimer’s Association(T-PEP-18-579974C,to BSS);a grant from the Richman Family Precision Medicine Center of Excellence in Alzheimer’s disease(to BSS and DK).KC and TRJ were Funded by NIH R25GM109441(Hopkins PREP).

摘　　要：Background Cognitive decline in Alzheimer’s disease(AD)is associated with hyperphosphorylated tau(pTau)propagation between neurons along synaptically connected networks,in part via extracellular vesicles(EVs).EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin.We report,for the first time,that human tau expression elevates brain ceramides and nSMase2 activity.Methods To determine the therapeutic benefit of inhibiting this elevation,we evaluated PDDC,the first potent,selective,orally bioavailable,and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model.Additionally,we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus(AAV)encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus.The contralateral transfer of the double mutant human tau to the dentate gyrus was monitored.We examined ceramide levels,histopathological changes,and pTau content within EVs isolated from the mouse plasma.Results Similar to human AD,the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity;both were completely normalized by PDDC treatment.The PS19 mice also exhibited elevated tau immunostaining,thinning of hippocampal neuronal cell layers,increased mossy fiber synaptophysin immunostaining,and glial activation,all of which were pathologic features of human AD.PDDC treatment reduced these changes.The plasma of PDDC-treated PS19 mice had reduced levels of neuronal-and microglial-derived EVs,the former carrying lower pTau levels,compared to untreated mice.In the tau propagation model,PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral side.Conclusions PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity,leading to the slowing of tau spread in AD mice.

关 键 词：Alzheimer’s disease Extracellular vesicles Neutral sphingomyelinase 2 TAU CERAMIDE 

分 类 号：R749.16[医药卫生—神经病学与精神病学] R-332[医药卫生—临床医学]