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Microglial-Targeted nSMase2 Inhibitor Fails to Reduce Tau Propagation in PS19 Mice

The progression of Alzheimer’s disease (AD) correlates with the propagation of hyperphosphorylated tau (pTau) from the entorhinal cortex to the hippocampus and neocortex. Neutral sphingomyelinase2 (nSMase2) is critical in the biosynthesis of extracellular vesicles (EVs), which play a role in pTau pr...

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Autores principales: Huang, Meixiang, Tallon, Carolyn, Zhu, Xiaolei, Huizar, Kaitlyn D. J., Picciolini, Silvia, Thomas, Ajit G., Tenora, Lukas, Liyanage, Wathsala, Rodà, Francesca, Gualerzi, Alice, Kannan, Rangaramanujam M., Bedoni, Marzia, Rais, Rana, Slusher, Barbara S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10536502/
https://www.ncbi.nlm.nih.gov/pubmed/37765332
http://dx.doi.org/10.3390/pharmaceutics15092364
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author Huang, Meixiang
Tallon, Carolyn
Zhu, Xiaolei
Huizar, Kaitlyn D. J.
Picciolini, Silvia
Thomas, Ajit G.
Tenora, Lukas
Liyanage, Wathsala
Rodà, Francesca
Gualerzi, Alice
Kannan, Rangaramanujam M.
Bedoni, Marzia
Rais, Rana
Slusher, Barbara S.
author_facet Huang, Meixiang
Tallon, Carolyn
Zhu, Xiaolei
Huizar, Kaitlyn D. J.
Picciolini, Silvia
Thomas, Ajit G.
Tenora, Lukas
Liyanage, Wathsala
Rodà, Francesca
Gualerzi, Alice
Kannan, Rangaramanujam M.
Bedoni, Marzia
Rais, Rana
Slusher, Barbara S.
author_sort Huang, Meixiang
collection PubMed
description The progression of Alzheimer’s disease (AD) correlates with the propagation of hyperphosphorylated tau (pTau) from the entorhinal cortex to the hippocampus and neocortex. Neutral sphingomyelinase2 (nSMase2) is critical in the biosynthesis of extracellular vesicles (EVs), which play a role in pTau propagation. We recently conjugated DPTIP, a potent nSMase2 inhibitor, to hydroxyl-PAMAM-dendrimer nanoparticles that can improve brain delivery. We showed that dendrimer-conjugated DPTIP (D–DPTIP) robustly inhibited the spread of pTau in an AAV-pTau propagation model. To further evaluate its efficacy, we tested D-DPTIP in the PS19 transgenic mouse model. Unexpectantly, D-DPTIP showed no beneficial effect. To understand this discrepancy, we assessed D-DPTIP’s brain localization. Using immunofluorescence and fluorescence-activated cell-sorting, D-DPTIP was found to be primarily internalized by microglia, where it selectively inhibited microglial nSMase2 activity with no effect on other cell types. Furthermore, D-DPTIP inhibited microglia-derived EV release into plasma without affecting other brain-derived EVs. We hypothesize that microglial targeting allowed D-DPTIP to inhibit tau propagation in the AAV-hTau model, where microglial EVs play a central role in propagation. However, in PS19 mice, where tau propagation is independent of microglial EVs, it had a limited effect. Our findings confirm microglial targeting with hydroxyl-PAMAM dendrimers and highlight the importance of understanding cell-specific mechanisms when designing targeted AD therapies.
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spelling pubmed-105365022023-09-29 Microglial-Targeted nSMase2 Inhibitor Fails to Reduce Tau Propagation in PS19 Mice Huang, Meixiang Tallon, Carolyn Zhu, Xiaolei Huizar, Kaitlyn D. J. Picciolini, Silvia Thomas, Ajit G. Tenora, Lukas Liyanage, Wathsala Rodà, Francesca Gualerzi, Alice Kannan, Rangaramanujam M. Bedoni, Marzia Rais, Rana Slusher, Barbara S. Pharmaceutics Article The progression of Alzheimer’s disease (AD) correlates with the propagation of hyperphosphorylated tau (pTau) from the entorhinal cortex to the hippocampus and neocortex. Neutral sphingomyelinase2 (nSMase2) is critical in the biosynthesis of extracellular vesicles (EVs), which play a role in pTau propagation. We recently conjugated DPTIP, a potent nSMase2 inhibitor, to hydroxyl-PAMAM-dendrimer nanoparticles that can improve brain delivery. We showed that dendrimer-conjugated DPTIP (D–DPTIP) robustly inhibited the spread of pTau in an AAV-pTau propagation model. To further evaluate its efficacy, we tested D-DPTIP in the PS19 transgenic mouse model. Unexpectantly, D-DPTIP showed no beneficial effect. To understand this discrepancy, we assessed D-DPTIP’s brain localization. Using immunofluorescence and fluorescence-activated cell-sorting, D-DPTIP was found to be primarily internalized by microglia, where it selectively inhibited microglial nSMase2 activity with no effect on other cell types. Furthermore, D-DPTIP inhibited microglia-derived EV release into plasma without affecting other brain-derived EVs. We hypothesize that microglial targeting allowed D-DPTIP to inhibit tau propagation in the AAV-hTau model, where microglial EVs play a central role in propagation. However, in PS19 mice, where tau propagation is independent of microglial EVs, it had a limited effect. Our findings confirm microglial targeting with hydroxyl-PAMAM dendrimers and highlight the importance of understanding cell-specific mechanisms when designing targeted AD therapies. MDPI 2023-09-21 /pmc/articles/PMC10536502/ /pubmed/37765332 http://dx.doi.org/10.3390/pharmaceutics15092364 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Meixiang
Tallon, Carolyn
Zhu, Xiaolei
Huizar, Kaitlyn D. J.
Picciolini, Silvia
Thomas, Ajit G.
Tenora, Lukas
Liyanage, Wathsala
Rodà, Francesca
Gualerzi, Alice
Kannan, Rangaramanujam M.
Bedoni, Marzia
Rais, Rana
Slusher, Barbara S.
Microglial-Targeted nSMase2 Inhibitor Fails to Reduce Tau Propagation in PS19 Mice
title Microglial-Targeted nSMase2 Inhibitor Fails to Reduce Tau Propagation in PS19 Mice
title_full Microglial-Targeted nSMase2 Inhibitor Fails to Reduce Tau Propagation in PS19 Mice
title_fullStr Microglial-Targeted nSMase2 Inhibitor Fails to Reduce Tau Propagation in PS19 Mice
title_full_unstemmed Microglial-Targeted nSMase2 Inhibitor Fails to Reduce Tau Propagation in PS19 Mice
title_short Microglial-Targeted nSMase2 Inhibitor Fails to Reduce Tau Propagation in PS19 Mice
title_sort microglial-targeted nsmase2 inhibitor fails to reduce tau propagation in ps19 mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10536502/
https://www.ncbi.nlm.nih.gov/pubmed/37765332
http://dx.doi.org/10.3390/pharmaceutics15092364
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