Alternative Anastrozole Target Protects Neurons in Preclinical Models of Inherited Tauopathy

Tauopathies, including Alzheimer's disease, are neurodegenerative diseases characterized by the pathological aggregation of the microtubule-associated protein Tau (MAPT). This study explores the neuroprotective properties of anastrozole, a clinical aromatase inhibitor, in both a Drosophila tauopathy model expressing human MAPTR406W and isogenic pairs of human induced pluripotent stem cell -derived cortical neurons expressing MAPT mutations. Initially identified through a Drosophila drug screen, anastrozole significantly reduced oxidative stress and Tau phosphorylation in neurons, independent of its aromatase inhibitory action. Further investigation revealed that anastrozole does not exert its protective effects through cholesterol metabolism or aromatase inhibition. Instead, screening in Drosophila identified CYP4V2 as a potential unintended target. Reducing its expression in MAPTR406W neurons recapitulated the protective effects against oxidative stress-mediated cell death. These findings position anastrozole and its off-target CYP4V2 as novel therapeutic avenues for Tauopathies and possibly in Alzheimer’s and related dementias by reducing Tau phosphorylation and oxidative stress.