Tau modification by the norepinephrine metabolite DOPEGAL stimulates its pathology and propagation.

ABSTRACT: The noradrenergic locus ceruleus (LC) is the first site of detectable tau pathology in Alzheimer's disease (AD), but the mechanisms underlying the selective vulnerability of the LC in AD have not been completely identified. In the present study, we show that DOPEGAL, a monoamine oxidase A (MAO-A) metabolite of norepinephrine (NE), reacts directly with the primary amine on the Lys353 residue of tau to stimulate its aggregation and facilitate its propagation. Inhibition of MAO-A or mutation of the Lys353 residue to arginine (Lys353Arg) decreases tau Lys353-DOPEGAL levels and diminishes tau pathology spreading. Wild-type tau preformed fibrils (PFFs) trigger Lys353-DOPEGAL formation, tau pathology propagation and cognitive impairment in MAPT transgenic mice, all of which are attenuated with PF

SUBMITTER: Kang SS 

PROVIDER: S-EPMC9018606 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature