Development of an AAV-based model of tauopathy targeting retinal ganglion cells and the mouse visual pathway to study the role of microglia in Tau pathology

Duwat, Charlotte; Léal, Pauline; Vautheny, Audrey; Aurégan, Gwenaëlle; Joséphine, Charlène; Gaillard, Marie-Claude; Hérard, Anne‐Sophie; Jan, Caroline; Gipchtein, Pauline; Mitja, Julien; Fouquet, Stéphane; Niepon, Marie-Laure; Hantraye, Philippe; Brouillet, Emmanuel; Bonvento, Gilles; Cambon, Karine; Bemelmans, Alexis-Pierre

doi:10.1016/j.nbd.2023.106116

Cited by 1 publication

(2 citation statements)

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“…The differential response of D-DPTIP between the AAV-hTau model and the PS19 mice can be attributed to the distinct mechanisms of tau spread in these two models. Recent findings from our lab and from other studies revealed a crucial contribution of microglia to the spread of tau in various AAV-hTau injection and propagation models [16,[39][40][41]. Notably, when microglia are depleted using the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 in an AAV propagation model, tau propagation is significantly halted.…”

Section: Discussionmentioning

confidence: 80%

“…Previous studies have used the well-characterized murine adeno-associated virus (AAV)-hTau seed-injection model to mimic pTau propagation observed in AD patients [ 32 , 33 , 34 , 35 , 36 , 37 ]. In these models, tau propagation was shown to be primarily mediated by microglial EVs [ 16 , 38 , 39 , 40 , 41 ]. Using a similar model, we recently demonstrated that D-DPTIP could significantly inhibit microglial nSMase2 activity and robustly block the spread of tau [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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

Huang,

Tallon,

Zhu

et al. 2023

Pharmaceutics

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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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Section: Discussionmentioning

confidence: 80%