A First-in-Class, Brain-Penetrant Small Molecule Inhibitor of the NOS1AP-Tau Interaction Rescues Tau Pathology In Vivo and Improves Cognition
Year: 2026
Type: preprint
Abstract: NOS1AP is a genetically validated driver of tau pathology in Alzheimer’s disease (AD), yet the NOS1AP-tau interaction itself has remained pharmacologically untargeted. We report CAPTOR-1 , a first-in-class small molecule that disrupts this interaction by binding a pocket in the N-terminal region of NOS1AP (residues 1-126). A drug-resistant NOS1AP Y16A/F42A variant that retained tau binding but exhibited a 78-fold reduction in CAPTOR-1 affinity provides genetic evidence supporting an on-target mechanism. In human iPSC-derived neurons, CAPTOR-1 dose-dependently reduces endogenous NOS1AP-tau association, tau seeding activity, and pathogenic tau phosphorylation, phenocopying genetic NOS1AP knockdown; these effects extend to neurons from patients with sporadic AD. Orally dosed CAPTOR-1 crosses the blood-brain barrier and engages NOS1AP in brain dose-dependently. Chronic oral dosing rescues pathology, synaptic function, and memory in a tauopathy model (PS19) and an amyloidosis model (APP/PS1), sparing wild-type littermates in both. This work establishes pharmacological disruption of the NOS1AP-tau interaction as a viable, disease-modifying strategy for AD and positions CAPTOR-1 as a biomarker-ready chemical probe (pTau217, neurofilament light) for translational studies.
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7220857861