Neutral sphingomyelinase-2 (nSMase2, encoded by SMPD3) operates at the plasma membrane and generates ceramide in response to inflammatory cytokines, oxidative stress, and glutamate excitotoxicity—all relevant to neurodegeneration. Unlike lysosomal ASMase (SMPD1), SMPD3 inhibition avoids lysosomal storage liabilities while targeting the ceramide pool most directly coupled to exosome biogenesis and apoptotic signaling. GW4869 is a reference inhibitor, but improved selectivity and CNS penetration are needed. The challenge requires: (1) pharmacological selectivity profile of best-in-class SMPD3 inhibitor vs. SMPD1, SMPD2, alkaline SMase; (2) ceramide reduction at synaptic membranes in cortical neurons vs. lysosomal ceramide; (3) 6-week treatment in tau-P301S mice measuring gliosis, synapse density, and cognitive behavior; (4) CSF ceramide/sphingomyelin ratio as PK/PD biomarker. Falsifiable prediction: selective SMPD3 inhibitor (≥50× selectivity over SMPD1) should reduce synaptic ceramide by ≥50% in cortical culture, reduce tau-P301S neuroinflammation score by ≥35%, and show no lysosomal cholesterol accumulation at 3× efficacious dose. Bounty tier: $750K mechanistic + in-vivo validation, sphingolipid neurotherapeutics.