Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Meixiang Huang
,
Carolyn Tallon
,
Xiaolei Zhu
ORCID logo ,
Kaitlyn DJ Huizar
,
Silvia Picciolini
ORCID logo ,
Ajit G. Thomas
,
Lukas Tenora
,
Wathsala Liyanage
,
Francesca Rodà
ORCID logo ,
Alice Gualerzi
ORCID logo ,
Rangaramanujam M. Kannan
,
Marzia Bedoni
ORCID logo ,
Rana Rais
ORCID logo ,
Barbara S. Slusher
* ORCID logo
Version 1 : Received: 11 August 2023 / Approved: 14 August 2023 / Online: 15 August 2023 (09:01:43 CEST)

A peer-reviewed article of this Preprint also exists.

Huang, M.; Tallon, C.; Zhu, X.; Huizar, K.D.J.; Picciolini, S.; Thomas, A.G.; Tenora, L.; Liyanage, W.; Rodà, F.; Gualerzi, A.; Kannan, R.M.; Bedoni, M.; Rais, R.; Slusher, B.S. Microglial-Targeted nSMase2 Inhibitor Fails to Reduce Tau Propagation in PS19 Mice. Pharmaceutics 2023, 15, 2364. Huang, M.; Tallon, C.; Zhu, X.; Huizar, K.D.J.; Picciolini, S.; Thomas, A.G.; Tenora, L.; Liyanage, W.; Rodà, F.; Gualerzi, A.; Kannan, R.M.; Bedoni, M.; Rais, R.; Slusher, B.S. Microglial-Targeted nSMase2 Inhibitor Fails to Reduce Tau Propagation in PS19 Mice. Pharmaceutics 2023, 15, 2364.

Abstract

Alzheimer’s disease(AD) progression 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 which can improve brain delivery. We showed that dendrimer-conjugated-DPTIP (D-DPTIP) robustly inhibited pTau spread 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.

Keywords

Alzheimer’s disease; DPTIP; hydroxyl PAMAM dendrimer; D-DPTIP; extracellular vesicles; neutral sphingomyelinase 2; tau

Subject

Biology and Life Sciences, Neuroscience and Neurology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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