Polyanionic peptibody ameliorates tau pathology and promotes neuronal proteostasis in a tau transgenic mouse model

The intraneuronal aggregation of tau is a key driver of pathogenesis in Alzheimer's disease and other tauopathies. The positively charged proline-rich region and microtubule-binding domain of tau are important for tubulin binding which enables axonal transport in physiological conditions. In disease, however, the positively charged repeat domains of such regions become exposed, facilitating tau-tau aggregation and other pathogenic tau-protein interactions which leads to neuronal dysfunction. Here, we generated a polyanionic peptide to electrostatically interact with tau and fused it to an inert single-chain variable fragment (scFv) antibody for improved peptide half-life and downstream intraneuronal expression. The resultant polyanionic peptibody, ACR12, was investigated in vitro and in tau transgenic mice for ability to prevent tau aggregation and associated disease phenotypes. In human neuroblastoma cells, ACR12 was stably expressed within the cytoplasm where it successfully engaged intracellular tau. DNA encoding ACR12 was then packaged into a brain-penetrant Adeno-associated virus, AAV-PHP.eB, for intravenous delivery into K3 tau transgenic mice. Such treatment facilitated long-term intraneuronal expression of ACR12 and reduced total and phosphorylated tau in the brain. ACR12 treatment in female K3 mice also restored deregulated neuronal proteins to wild-type levels. This study highlights the role of positively charged domains in tau pathogenesis and demonstrates the therapeutic utility of electrostatic tau interactors.