P1‐237: POST‐TRANSLATIONAL MODIFICATIONS OF TAU IN ALZHEIMER'S DISEASE: A POSTMORTEM STUDY IN HUMANS

In Alzheimer's disease (AD), tau undergoes many post-translational modifications (PTMs) by the activity of kinases, acetyltransferases, and caspases leading to hyperphosphorylated-tau (p-Tau), acetylated-tau (a-Tau), and cleaved-tau (c-Tau), respectively. Proteomic analysis has highlighted increased levels of several Tau PTMs in AD; however, the anatomic distribution of these PTMs, their progression across disease stages, and the anatomic and temporal relationships between tau PTMs remain unclear. The entorhinal cortex (EC) and middle frontal gyrus (MFG) were sampled from cases at Braak stages I-II (n=6) and Braak stages V-VI (n=6) from the Biobank for Aging Studies at the University of São Paulo and the Neurodegenerative Disease Brain Bank at the University of California, San Francisco. Fixed paraffin-embedded sections were immunofluorescently labeled for Phospho-Ser202/Thr205 tau (AT8, 1:300), Acetyl-Lys274 tau (mAb359, 1:300), TauΔAsp401 (RbGN10635, 1:150, gift of Andrea LeBlanc, Bloomfield Centre for Research in Aging, Montreal, Canada), and DAPI. Positive neurons in three 100x100μm fields were counted in each section. The number of a-Tau+ neurons correlates more closely with the number of c-Tau+ neurons than the number of p-Tau+ neurons does (Table 1). The frequencies of PTMs, the percent overlap between PTMs, and significance of difference between early and late Braak stages are depicted in Table 2. Caspase-6 cleavage at Asp401 facilitates the formation of paired helical filaments (PHF). The PTMs that trigger this caspase activity are unclear. These data suggest that acetylation of tau at Lys274 correlates better with cleavage by caspase-6 than phosphorylation of tau at Ser202/Thr205 does. While there is colocalization between p-Tau and c-Tau, the majority of neurons positive for both p-Tau and c-Tau are also positive for a-Tau, suggesting that caspase-mediated cleavage of tau in these neurons may be primarily induced by acetylation, rather than phosphorylation. These preliminary data highlight that the acetylation of tau represents a key step in AD pathobiology and warrants further study . Middle frontal gyrus in a Braak stage VI case. a, c-Tau and Hoechst 33342; b, a-Tau and Hoechst 33342; c, p-Tau and Hoechst 33342; d, a-Tau and Hoechst 33342; e, c-Tau and Hoechst 33342; f, p-Tau and Hoechst 33342; g, a-Tau (green) c-Tau (yellow) p-Tau (red) and Hoechst 33342 (blue).

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