The neutral sphingomyelinase 2 inhibitor PDDC reduces tau burden in Alzheimer’s disease mice

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by worsening cognitive impairment with amyloid and tau deposition spreading throughout the brain in a “prion‐like” manner. Mounting evidence suggests extracellular vesicles (EVs) can act as vectors to propagate these pathogenic proteins along connectivity pathways. Several studies have demonstrated that inhibiting neutral sphingomyelinase 2 (nSMase2) reduces the level of tau and amyloid in the brain. Despite these promising findings, current nSMase2 inhibitors are not suitable for clinical development given their lack of potency, solubility, and/or limited brain penetration. We recently discovered phenyl (R)‐(1‐(3‐(3,4‐dimethoxyphenyl)‐2,6‐dimethylimidazo[1,2‐b] pyridazin‐8‐yl) pyrrolidin‐3‐yl) carbamate (PDDC), the first selective, potent nSMase2 inhibitor (IC50 = 300nM), with excellent oral bioavailability (%F = 88) and brain penetration (AUCbrain/AUCplasma = 0.60). We demonstrated that PDDC was able to inhibit EV release both in vitro and in vivo.MethodTo facilitate chronic oral efficacy studies, PDDC was incorporated into mouse chow which provided consistent brain exposure levels above its nSMase IC50 over a 24h time period. 4‐month old PS19 mice were fed either vehicle or PDDC chow for 5 months and their brains were collected for nSMase2 activity and tau protein level assessments.ResultVehicle treated PS19 mice had elevated nSMase2 activity levels compared to WT controls, which was completely normalized by PDDC treatment. Total tau and Thr181 phosphorylated tau were elevated in PS19 mice and significantly reduced in PDDC treated animals. Decreases in Thr217 and Ser202/Thr205 phosphorylated tau were also observed in PDDC‐treated mice, but the effect did not reach statistical significance. We are currently expanding these studies to evaluate PDDC in a rapid tau propagation model where AAV‐P301LhTau vectors are being unilaterally injected into the brains of WT mice and the propagation of phosphorylated tau to the contralateral side is bring quantified.ConclusionPDDC reduces the levels of total and pTau Thr181 in AD mice supporting its potential use as a novel therapeutic for the treatment of AD.