Immunotherapy Against Acetylated Tau at K280 Ameliorates Behavioral Impairments and Pathologies of Tau Transgenic Mouse

Abstract Background : Tau is gaining attention as a target of therapeutic antibodies for Alzheimer's disease (AD) and other tauopathies but it was recently of debate which epitope on tau has therapeutic potency. While the hexapeptide 275VQIINK280 is a critical region for tau aggregation and K280 is acetylated in various tauopathies including AD, there has been no immunotherapy targeting acetylated K280. Methods : Acetylated K280 was first chosen as therapeutic target from small pilot studies comparing in vivo behavioral efficacy of tau transgenic mice by immunizing with several putatively pathogenic epitopes such as acetylated or phosphorylated or cleaved tau. Results : Therapeutic efficacy in tau transgenic mice was further evaluated with behavior, pathology and biochemical experiments after either active immunization with tau peptide acetylated at K280 or passive immunization with anti-tau antibody targeting K280 acetylation. Vaccination with tau peptide acetylated at K280 or antibody (Y01) targeting it ameliorated memory impairments and pathology in tau transgenic mice via intracerebroventricular or intraperitoneal route. Conclusions : This study showed that acetylated K280 tau is a good therapeutic target and Y01 could be a novel therapeutic antibody for AD and other tauopathies.