Alternative Anastrozole Target CYP4V2 Impairs Neurons in Preclinical Models of Inherited Tauopathy

Tauopathies, including Alzheimer 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 MAPT ^R406W and isogenic pairs of human induced pluripotent stem cell-derived cortical neurons expressing MAPT mutations. The Aromatase inhibitor anastrozole, initially identified in a Drosophila MAPT ^R406W drug screen, reduced oxidative stress and Tau phosphorylation in cultured cortical neurons. Its protective effects were not mediated by Aromatase activity or cholesterol metabolism: screening in Drosophila identified CYP4V2 as a potential off-target. Knockdown of CYP4V2 in MAPT ^R406W neurons recapitulated protection against oxidative stress-induced cell death. These findings position anastrozole and its offtarget CYP4V2 as novel therapeutic avenues for primary tauopathies and potentially Alzheimer’s disease and related dementias by reducing Tau phosphorylation and susceptibility to oxidative stress.