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

Translational Neurodegeneration 2023年第1期12卷 70-89页

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 Johns Hopkins Drug Discovery Johns Hopkins University School of MedicineBaltimoreMD 21205USA Neurology Johns Hopkins University School of MedicineBaltimoreMD 21205USA Cell Biology Johns Hopkins University School of MedicineBaltimoreMD 21205USA Oncology Johns Hopkins University School of MedicineBaltimoreMD 21205USA Medicine Johns Hopkins University School of MedicineBaltimoreMD 21205USA Pharmacology and Molecular Sciences Johns Hopkins University School of MedicineBaltimoreMD 21205USA Psychiatry and Behavioral Science Johns Hopkins University School of Medicine855 N.Wolfe StreetRangos 278BaltimoreMD 21205USA Intramural Research Program Laboratory of Clinical InvestigationNational Institute on AgingNational Institutes of Health251 Bayview BlvdSte 8C228BaltimoreMD 21224USA Johns Hopkins University School of Medicine 600 N.Wolfe StreetPathology 517BaltimoreMD 21287USA

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 *** report,for the first time,that human tau expression elevates brain ceramides and nSMase2 *** 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 ***,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 *** contralateral transfer of the double mutant human tau to the dentate gyrus was *** examined ceramide levels,histopathological changes,and pTau content within EVs isolated from the mouse *** Similar to human AD,the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity;both were completely normalized by PDDC *** 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 *** treatment reduced these *** plasma of PDDC-treated PS19 mice had reduced levels of neuronal-and microglial-derived EVs,the former carrying lower pTau levels,compared to untreated *** the tau propagation model,PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral *** PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity,leading to the slo

关键词： Alzheimer’s disease Extracellular vesicles Neutral sphingomyelinase 2 Tau Ceramide

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