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Effects of p38α MAP kinase inhibition on the neurodegenerative phenotype of the Ts2 Down Syndrome mouse model

Abstract ID: 35400

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Ying Jiang, PhD1,2; Philip Stavrides, MS1; Sandipkumar Darji, MS1; Dun-Sheng Yang, PhD1,2; Cynthia Bleiwas, MS1; John Smiley, PhD1,2; Ursula Germann, PhD3; John Alam, MD3 and Ralph Nixon, MD, PhD1,2, (1)Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA, (2)NYU Langone Medical Center, New York, NY, USA, (3)EIP Pharma Inc., Cambridge, MA, USA

Background: P38α MAP kinase is implicated in the pathogenesis of synaptic dysfunction in Alzheimer’s disease (AD) (Colié, 2017), partially due to increased BACE1 expression resulting from p38α-mediated impairment of autophagy-lysosomal protein degradation (Schnöder, 2016). Neflamapimod, an oral p38α inhibitor, reverses spatial learning deficits in aged rats (Alam, 2015) and preliminary clinical evidence indicates it may improve episodic memory in AD (Scheltens, 2018). Neflamapimod is being evaluated in a phase 2b clinical study in Early AD. We previously showed neflamapimod reverses APP-induced endocytic dysfunction in Down Syndrome (DS) human fibroblasts (AAIC, 2017). Herein, we report on in-vivo effects of neflamapimod in Ts2 mice that model DS and develop typical AD pathology, including endocytic abnormalities and basal forebrain cholinergic degeneration (Jiang, 2016). Method: Wild-type (WT) or Ts2 mice treated for 28 days, twice-daily, with vehicle (1%PluronicF108) or 3mg/kg neflamapimod in vehicle (n=8-10 per group; 1:1 female/male). Treatment initiated at 4.7-6.4 months of age, when endosomal pathology is evident and cholinergic neuronal loss is developing in Ts2 mice. Cortical Rab5+ endosomal number and size, and medial septal nucleus (MSN) choline-acetyltransferase (ChAT)+ neurons quantitated per Jiang, 2016 (Neurobiol Aging39:90-98). Result: Consistent with the literature, numbers of medium (0.51-1.4 μm2)and large (>1.4 μm2) Rab5+ early-endosomes were increased and ChAT+ neurons in MSN were decreased in vehicle-treated Ts2 mice compared to vehicle-treated WT mice (p<0.001 for all comparisons). These Ts2 phenotypes were reversed by neflamapimod treatment. The number of medium (p<0.01) and large (p<0.001) Rab5+ early-endosomes declined and ChAT+ neurons in MSN were increased (p<0.001; see figure) in neflamapimod-treated Ts2 mice compared to vehicle-treated Ts2 mice. For both large Rab5+ endosomes and ChAT+ neurons, the quantitative measures in neflamapimod-treated Ts2 mice were similar to those seen in vehicle-treated WT mice, while neflamapimod treatment had no effect on WT mice. Conclusion: The findings indicate that p38α antagonism could treat the neurodegenerative process beyond reversing synaptic dysfunction. As p38α activates Rab5 (Cavalli, 2001), as well the central role of Rab5 in APP-induced endolysosomal dysfunction (Nixon, 2017), these effects of neflamapimod may be mediated via reversal of APP-βCTF-induced Rab5 hyperactivation (Kim, 2016; PMID:26194181). Support: NIA P01AG017617-1(RAN); R01 AG062376(RAN)