The presence of paired helical fragments formed by hyperphosphorylation of microtubule-associated protein Tau is a hallmark pathology of AD (Raskin, Cummings, Hardy, Schuh, & Dean, 2015). The Tau protein can be phosphorylated at a combined total of 85 serine, threonine, and tyrosine residues that constitute about 20% of the total protein (Tenreiro, Eckermann, & Outeiro, 2014); however, there appears to be specificity with respect to disease progression. In late-stage AD (Braak stage V/VI; Severe dementia, anxiety, depression) phosphorylation of a cluster of Tau residues termed AT8 (Ser199/Ser202/Thr205) is elevated in cortical brain tissue from human AD patients from 4- to 13-fold over controls (Neddens et al., 2018). Strikingly, analysis of the transentorhinal cortex showed that Tau phosphorylation at Ser199 was elevated as much as 160-fold over healthy controls suggesting a high degree of relevance for the Ser199 residue in disease progression (Neddens et al., 2018).
