NSMase2 inhibition reduces tau propagation in Alzheimer’s Disease mouse models

Abstract

AbstractBackgroundAlzheimer’s Disease (AD) is the most common form of dementia worldwide and is characterized by progressive neurodegeneration and cognitive decline, putatively driven by the accumulation Amyloid‐b and hyperphosphorylated Tau. Clinical trial successes focusing on reducing Amyloid‐b plaque levels in patient brains have been modest, spurring a renewed focus on tau. Tau spreads throughout the brain along anatomical pathways, correlating strongly with the disease progression severity. Recent evidence has highlighted extracellular vesicles (EVs) in enabling transcellular transmission of pathological tau in the brain in a ‘prion‐like’ manner and identified the inhibition of EV biogenesis via small‐molecule inhibitors of nSMase2 as a potential therapeutic avenue. However, presently available tool compounds are unsuitable for clinical development.MethodTo improve upon current inhibitors, we performed high‐throughput screening followed by extensive chemistry and identified two classes of compounds. The first, PDDC, has excellent potency, oral bioavailability, and brain penetration, as well as in vitro and in vivo EV inhibition. The second, DPTIP, has higher potency, but poor oral pharmacokinetics and modest brain penetration. To circumvent these limitations, we conjugated DPTIP to a brain‐targeting hydroxyl‐dendrimer delivery system (D‐DPTIP) and demonstrated CNS target engagement following oral dosing. We then chronically administered PDDC and D‐DPTIP to PS19 transgenic mice and WT mice seeded with an AAV‐hTau vector unilaterally stereotaxically injected into the CA1 hippocampal region. After chronic dosing, we quantified the levels of phosphorylated tau in the hippocampus in the PS19s and the contralateral dentate gyrus in the AAV‐hTau seeded model. We also characterized isolated neuronally‐derived plasma EVs from these mice.ResultPS19 mice treated with PDDC had significantly reduced hippocampal tau and increased neuronal counts compared with vehicle. Additionally, PDDC treatment reduced the release of neuronally‐derived EVs into circulation with lower tau level trends. Similarly, seeded mice treated with either PDDC or D‐DPTIP had reduced tau staining intensity in the contralateral dentate gyrus. Importantly, neither compound induced significant toxicity in either model.ConclusionObserving significant reductions in tau burden in two separate AD models provides proof of concept for nSMase2 inhibition in slowing tau propagation, highlighting the promise of tested compounds as potential AD therapeutics.