Clearing truncated tau protein restores neuronal function and prevents microglia activation in tauopathy mice

Tau protein truncated at Asp 421 is a characteristic feature of Alzheimer's disease and other tauopathies. Here, we show that a monoclonal antibody against Asp421, 5G2, cleared insoluble tau in the brains of JNPL3 mice, decreased tau levels in brain interstitial fluid in awake JNPL3 mice, improved in vivo neuronal function, and reduced microglial Iba-1 expression in PS19 mice, in which neuronal tau aggregation and dysfunction occurred earlier than microglial activation. For mechanistic insight using culture models, 5G2 prevented tau-mediated toxicity, cleared extra- and intracellular tau, and prevented microgliosis. TRIM21 knockdown reduced neuronal retention of tau antibodies and their acute but not longer-term efficacy. Inhibition of the endosomal/lysosomal pathway but not the proteasomal pathway blocked 5G2-mediated neuroprotection and tau clearance. These findings support targeting the Asp421 truncated tau protein to treat tauopathies, indicate that tau-associated neuronal dysfunction precedes microglial activation, and that intraneuronal antibody-mediated tau clearance is mostly via the lysosomes.