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

Meixiang Huang; Carolyn Tallon; Xiaolei Zhu; Kaitlyn D J Huizar; Silvia Picciolini; Ajit G Thomas; Lukas Tenora; Wathsala Liyanage; Francesca Rodà; Alice Gualerzi; Rangaramanujam M Kannan; Marzia Bedoni; Rana Rais; Barbara S Slusher

doi:10.3390/pharmaceutics15092364

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

Pharmaceutics. 2023 Sep 21;15(9):2364. doi: 10.3390/pharmaceutics15092364.

Authors

Meixiang Huang^{1

2}, Carolyn Tallon^{1

2}, Xiaolei Zhu^{1

3}, Kaitlyn D J Huizar¹, Silvia Picciolini⁴, Ajit G Thomas^{1

2}, Lukas Tenora^{1

2}, Wathsala Liyanage⁵, Francesca Rodà^{4

6}, Alice Gualerzi⁴, Rangaramanujam M Kannan^{5

7}, Marzia Bedoni⁴, Rana Rais^{1

2

8}, Barbara S Slusher^{1

2

3

8

9}

Affiliations

¹ Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ IRCCS Fondazione Don Carlo Gnocchi ONLUS, Laboratory of Nanomedicine and Clinical Biophotonics (LABION), 20148 Milan, Italy.
⁵ Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
⁶ Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 42100 Modena, Italy.
⁷ Department of Chemical and Biomolecular Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁹ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Abstract

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.

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

Abstract

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