Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model
Abstract 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 fr...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-12-01
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| Series: | Translational Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40035-023-00383-9 |
| _version_ | 1797397841154408448 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Carolyn Tallon |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-09T01:16:01Z |
| format | Article |
| id | doaj.art-d163368f208644598366636e9b045806 |
| institution | Directory Open Access Journal |
| issn | 2047-9158 |
| language | English |
| last_indexed | 2024-03-09T01:16:01Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Translational Neurodegeneration |
| spelling | doaj.art-d163368f208644598366636e9b0458062023-12-10T12:29:26ZengBMCTranslational Neurodegeneration2047-91582023-12-0112112010.1186/s40035-023-00383-9Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse modelCarolyn Tallon0Benjamin J. Bell1Medhinee M. Malvankar2Pragney Deme3Carlos Nogueras-Ortiz4Erden Eren5Ajit G. Thomas6Kristen R. Hollinger7Arindom Pal8Maja Mustapic9Meixiang Huang10Kaleem Coleman11Tawnjerae R. Joe12Rana Rais13Norman J. Haughey14Dimitrios Kapogiannis15Barbara S. Slusher16Johns Hopkins Drug Discovery, Johns Hopkins University School of MedicineJohns Hopkins Drug Discovery, Johns Hopkins University School of MedicineJohns Hopkins Drug Discovery, Johns Hopkins University School of MedicineNeurology, Johns Hopkins University School of MedicineIntramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of HealthIntramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of HealthJohns Hopkins Drug Discovery, Johns Hopkins University School of MedicineJohns Hopkins Drug Discovery, Johns Hopkins University School of MedicineJohns Hopkins Drug Discovery, Johns Hopkins University School of MedicineIntramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of HealthJohns Hopkins Drug Discovery, Johns Hopkins University School of MedicineJohns Hopkins Drug Discovery, Johns Hopkins University School of MedicineJohns Hopkins Drug Discovery, Johns Hopkins University School of MedicineJohns Hopkins Drug Discovery, Johns Hopkins University School of MedicineNeurology, Johns Hopkins University School of MedicineNeurology, Johns Hopkins University School of MedicineJohns Hopkins Drug Discovery, Johns Hopkins University School of MedicineAbstract 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.https://doi.org/10.1186/s40035-023-00383-9Alzheimer’s diseaseExtracellular vesiclesNeutral sphingomyelinase 2TauCeramide |
| spellingShingle | 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 Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model Translational Neurodegeneration Alzheimer’s disease Extracellular vesicles Neutral sphingomyelinase 2 Tau Ceramide |
| title | Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model |
| title_full | Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model |
| title_fullStr | Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model |
| title_full_unstemmed | Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model |
| title_short | Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model |
| title_sort | inhibiting tau induced elevated nsmase2 activity and ceramides is therapeutic in an alzheimer s disease mouse model |
| topic | Alzheimer’s disease Extracellular vesicles Neutral sphingomyelinase 2 Tau Ceramide |
| url | https://doi.org/10.1186/s40035-023-00383-9 |
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