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

Abstract

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 transgenic mice expressing human amyloid precursor protein (hAPP). We used mass spectrometry to characterize the post-translational modification of endogenous tau isolated from wild-type and hAPP mice. We identified seven types of tau modifications at 63 sites in wild-type mice. Wild-type 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-linked N-acetylglucosamine (O-GlcNAc) modification of endogenous tau. The complex post-translational modification of physiological tau suggests that tau is regulated by diverse mechanisms.

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

“…Finally, it is also possible that posttranslational modifications (PTMs) on tau facilitate protein misfolding into distinct prion strains. A large number of PTMs have been identified on tau isolated from both human and Tg mouse samples, including multiple sites for phosphorylation, acetylation, ubiquitination, and O-glycosylation (60)(61)(62). However, none of these differences have been consistently detected in distinct patient groups in a manner that would explain the differences observed here.…”

Tau protein liquid–liquid phase separation can initiate tau aggregation

“…For example, phosphorylation regulates LLPS of nephrine (Li et al , 2012), FUS (Monahan et al , 2017), and RNA binding protein CPEB4 (Guillén‐Boixet et al , 2016). Phosphorylation is also the major type of PTMs in tau (Morris et al , 2015), and more than 80 potential phosphorylation sites can be found in the amino acid sequence of tau (Reynolds et al , 2008). …”

Identification of the Tau phosphorylation pattern that drives its aggregation

“…Recent progress in mass spectrometry has improved the coverage of Tau's possible PTMs (40,41), but antibodies remain the workhorse in a clinical setting. Notably, Braak staging, whereby the cognitive decline of deceased patients is correlated with the extent of the lesions in their brain, has been standardized on the basis of immunochemistry with the AT8 antibody (10).…”