Carolyn Tallon, Benjamin J Bell, Medhinee M Malvankar, Pragney Deme, Carlos Nogueras-Ortiz, Erden Eren, Ajit G Thomas, Kristen R Hollinger, Arindom Pal, Maja Mustapic, Meixiang Huang, Kaleem Coleman, Tawnjerae R Joe, Rana Rais, Norman J Haughey, Dimitrios Kapogiannis, Barbara S Slusher
BACKGROUND: Cognitive decline in Alzheimer's disease (AD) is associated with hyperphosphorylated tau (pTau) propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EVs). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2 (nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that human tau expression elevates brain ceramides and nSMase2 activity. METHODS: To determine the therapeutic benefit of inhibiting this elevation, we evaluated PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model...
December 4, 2023: Translational Neurodegeneration