N-terminally acetylated Met11-Tau: a new pathological truncated Tau species with functional relevance in Alzheimer's disease

Abstract Background Tauopathies are a group of neurodegenerative diseases, including Alzheimer’s disease (AD), characterized by progressive accumulation of pathological Tau proteins. Among the diverse Tau species, truncated variants are emerging as key contributors, yet their identity remains elusive, particularly for the N-terminal truncated ones. The present study identifies and characterizes a novel N-terminally truncated and N-alpha-acetylated form of the Tau protein, named AcMet11-Tau. Methods We identified AcMet11-Tau by further analyses of previous proteomic data (capillary liquid chromatography-tandem mass spectrometry). We developed a monoclonal antibody, termed 2H2D11, by hybridoma method. The specificity of 2H2D11 was validated by ELISA, Western blot and immunohistochemistry. Expression of AcMet11-Tau in transgenic mouse model of Tau pathology and postmortem brain tissues was analyzed by ELISA and/or immunohistochemistry. Overexpression of AcMet11-Tau in the mouse brain was achieved by stereotaxic injections of lentiviral vectors carrying the coding sequence in the hippocampus. To neutralize AcMet11-Tau, transgenic mice received repeated intraperitoneal immunizations with either 2H2D11 or control antibody. The effects on Tau pathology were assessed by immunohistochemistry, qPCR, and behavioral assays. Results Using 2H2D11, the newly developed antibody specifically targeting the AcMet11-Tau variant, we demonstrated that this species accumulated early in degenerating neurons in both transgenic mouse models of AD-related Tau pathology and post-mortem brain tissues from AD patients. Importantly, in vivo functional experiments revealed that expression of this truncated Tau species exacerbated Tau pathology in the transgenic mice, whereas targeted immunotherapeutic with the specific 2H2D11 antibody significantly reduced pathological Tau accumulation and prevented associated memory impairments. Conclusion These findings position this newly identified Tau variant as a marker of neurofibrillary degeneration and a Tau species that contributes to disease-associated pathological processes, supporting its potential as a therapeutic target in Tau-related disorders, notably AD.