Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice

Abstract

Alzheimer’s disease (AD) is characterized by the progressive accumulation of amyloid-β and hyperphosphorylated tau (pTau), which can spread throughout the brain via extracellular vesicles (EVs). Membrane ceramide enrichment regulated by the enzyme neutral sphingomyelinase 2 (nSMase2) is a critical component of at least one EV biogenesis pathway. Our group recently identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), the most potent (30 nM) and selective inhibitor of nSMase2 reported to date. However, DPTIP exhibits poor oral pharmacokinetics (PK), modest brain penetration, and rapid clearance, limiting its clinical translation. To enhance its PK properties, we conjugated DPTIP to a hydroxyl-PAMAM dendrimer delivery system, creating dendrimer-DPTIP (D-DPTIP). In an acute brain injury model, orally administered D-DPTIP significantly reduced the intra-striatal IL-1β-induced increase in plasma EVs up to 72 h post-dose, while oral DPTIP had a limited effect. In a mouse tau propagation model, where a mutant hTau (P301L/S320F) containing adeno-associated virus was unilaterally seeded into the hippocampus, oral D-DPTIP (dosed 3× weekly) significantly inhibited brain nSMase2 activity and blocked the spread of pTau to the contralateral hippocampus. These data demonstrate that dendrimer conjugation of DPTIP improves its PK properties, resulting in significant inhibition of EV propagation of pTau in mice. Dendrimer-based delivery of DPTIP has the potential to be an exciting new therapeutic for AD.

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

“…Upon oral administration of DPTIP to an AD mice model, this conjugate inhibited neuroinflammation and tau progression in the brain by reducing the pathogenic EV population. 94 The same group has recently identifed another orally bioactive drug, PDDC, which targets nSMase2 and reduces AD symptoms, again in a EVdependent manner, in the PS19 AD mouse model. 95 However, the exact mechanisms were not commented upon, but the study does pave the way to EV-targeting therapies.…”

“…Indeed, the study by Tallun et al used the nSMase2 targeting by using a dendrimer conjugated with a selective inhibitor of the enzyme, DPTIP (2,6-dimethoxy-4-(5-phenyl-4-thiophen-2-yl-1H-imidazol-2-yl)-phenol). Upon oral administration of DPTIP to an AD mice model, this conjugate inhibited neuroinflammation and tau progression in the brain by reducing the pathogenic EV population . The same group has recently identifed another orally bioactive drug, PDDC, which targets nSMase2 and reduces AD symptoms, again in a EV-dependent manner, in the PS19 AD mouse model .…”

Advanced polymeric dendrimers in the management of Alzheimer's disease

“…SAMP8-APP/ PS1 mice have been shown to develop many pathological features associated with Alzheimer disease, which is characterized by severe amyloid deposition, neuronal loss and behavioral impairment. 78,79 Research on dementia has focused in particular on the SAMP8 sub strain because it exhibits age-related learning and memory prob- 80,81 The significance is multiple therapy options have been investigated in these mice using the SAMP8 strain, which is consistent with the idea that SAMP8 cognitive abnormalities are related to Aβ (Amyloidβ)-associated oxidative stress.…”

“…Congo red staining used which revealed that amyloidosis was found in the cortex and hippocampus of C57‐APP/PS1, SAMP8‐wild‐type and SAMP8‐APP/PS1. SAMP8‐APP/PS1 mice have been shown to develop many pathological features associated with Alzheimer disease, which is characterized by severe amyloid deposition, neuronal loss and behavioral impairment 78,79 …”

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model

“…The enzyme neutral sphingomyelinase 2 (nSMase2) cleaves sphingomyelin into ceramide, which enriches in the plasma membrane enhancing membrane curvature, resulting in EV budding [ 12 , 13 ]. Studies from our laboratory [ 14 , 15 ] and others [ 16 , 17 ] using nSMase2 genetic knock-down as well as structurally distinct small molecule inhibitors have demonstrated that inhibition of nSMase2 halts the spread of pTau. Although these data are supportive of nSMase2 inhibition as a therapeutic approach, there are no available inhibitors suitable for clinical development.…”