Novel Acetylated Tau Immunotherapy for Alzheimer's disease

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PROJECT SUMMARY/ABSTRACT: Alzheimer’s disease (AD) is a fatal, age-progressive neurodegenerative disease affecting nearly 6 million patients in the US. Currently, there is no cure for AD, and existing clinical trials have largely failed. This calls for the need to investigate new avenues to combat this disease. Recently, we and others have focused on post-translational modifications (PTM) of tau protein that mediate progression of tauopathies including AD. We identified acetylated tau as a key feature of nearly all AD patients and elucidated several pathways through which tau acetylation mediates toxicity including insoluble tau fibril formation, promoting aberrant tau hyper- phosphorylation, and causing dissociation of tau from microtubule (MTs). Furthermore, loss of key deacetylases that suppress tau acetylation including a sirtuin (SIRT1) and in our unpublished studies, the deacetylase HDAC6, is sufficient to exacerbate AD phenotypes in mice. We hypothesize that acetylated tau (Ac-Tau) represents a novel pathological strain that can be exploited therapeutically. Here, we will employ a first-of-its-kind preclinical immunotherapy study to target acetylated tau in an AD mouse model characterized by combined tau tangles and amyloid plaques. This model will better recapitulate human AD in which both tau and amyloid beta pathologies are present. By employing diverse, interdisciplinary approaches afforded by excellent UNC core facilities and collaborations, we will validate whether Ac-Tau immunotherapy can rescue AD-like neurodegeneration and cognitive decline. In Aim 1, we will screen >30 candidate monoclonal mouse antibodies via a newly developed in vitro high-throughput microscopy pipeline in tau-transfected cells to determine which candidate acetyl-tau antibodies against two specific sites (commonly observed in AD patients; K280 and K311) are most suitable for immunotherapy based on specificity and sensitivity for Ac-Tau. Preliminary data has confirmed that several antibodies are highly specific and promising. Given that Ac-Tau has been suggested as a disease-specific marker, we will investigate the utility of the Ac-tau antibodies for the detection of CSF-tau as a new AD biomarker. In Aim 2, using our most promising candidate antibodies for Ac-Tau, we will carry out an in vivo Ac-Tau immunotherapy trial in plaque/tangle bearing PS19/5xFAD mice at both early, preventative (3-6 months) and late (6-9 months) timepoints. We will perform biochemical and histological assays to assess key hallmarks of AD pathology and neurodegeneration followed by a rigorous evaluation of cognition, learning, and survival following Ac-Tau based immunotherapy. This project outlines the first in vivo immunotherapy study targeting Ac-Tau, which could potentially provide a new AD therapeutic and prognostic biomarker for use in the clinic. Furthermore, this proposal outlines a collaborative, comprehensive, and valuable post-doctoral training opportunity.