Tau post-translational modifications in wildtype and human amyloid precursor protein transgenic mice

The microtubule-associated protein tau has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Reducing tau levels ameliorates AD-related synaptic, network, and behavioral abnormalities in human amyloid precursor protein (hAPP) transgenic mice. We used mass spectrometry to characterize the post-translational modification of endogenous tau isolated from wildtype and hAPP mice. We identified seven types of tau modifications at 63 sites in wildtype mice. Wildtype and hAPP mice had similar modifications, supporting the hypothesis that neuronal dysfunction in hAPP mice is enabled by physiological forms of tau. Our findings provide clear evidence for acetylation and ubiquitination of the same lysine residues; some sites were also targeted by lysine methylation. Our findings refute the hypothesis of extensive O-GlcNAc modification of endogenous tau. The complex post-translational modification of physiological tau suggests that tau is regulated by diverse mechanisms.