Microglial‐targeted nSMase2 inhibitor fails to reduce tau spread in the animal model of Alzheimer’s disease

• DOI: 10.1002/alz.091930
• Publication Date: 2025-01-09T10:05:33Z
• Authors: Meixiang Huang; Carolyn Tallon; Xiaolei Zhu; Kaitlyn Huizar; Silvia Piccirillo; Ajit G Thomas; Lukas Tenora; Wathsala Liyanage; Francesca Roda; Alice Gualerzi; Rangaramanujam M ...; Marzia Bedoni; Rana Rais; Barbara S Slusher
• Keywords: Tauopathy

Abstract Background Cognitive decline associated with Alzheimer’s disease (AD) correlates hyperphosphorylated tau (pTau) propagating between neurons along networks connected by synapses. It has been hypothesized this transcellular transmission occurs partially extracellular vesicles (EVs). Both genetic and pharmacological inhibition of nSMase2 found to inhibit EV biogenesis pTau propagation. However, the lack suitable inhibitors for clinical development a challenge. In our lab, highly selective nM potency inhibitor, termed DPTIP, was identified through high‐throughput campaign. it poor oral pharmacokinetics (PK), modest brain penetration, rapid clearance, limiting its translation. To improve PK properties, we conjugated hydroxyl‐PAMAM dendrimer delivery system, creating dendrimer‐DPTIP (D‐DPTIP), which selectively targets microglia. previous studies, using murine AAV‐hTau injection propagation model, showed that administration D‐DPTIP significantly inhibited spread. study extended those studies evaluate in Tau P301S (PS19) transgenic mice. Method PS19 mice were chronically dosed 20 weeks. Subsequently cognitive function evaluated Y‐maze Novel Object Recognition tests, hippocampal volume measured MRI. Total levels quantified immunoblotting. Immunofluorescent staining fluorescence‐activated cell sorting (FACS) employed identify types responsible internalization. target engagement assays conducted both CD11b+ (microglial) CD11b‐ (non‐microglial cells). Surface plasmon resonance imaging (SPRi) used characterize origin (EVs) released into plasma ± treatment. Result tau, pTau, deficits, loss not altered treatment be co‐localized microglia decreased activity cells. SPRi analysis decrease activated microglia‐derived EVs following Conclusion inhibits Consequently, seeded model where microglial play central role, successfully effectiveness is limited mice, neuronal‐mediated thought predominant.