Cleavage and conformational changes of tau protein follow phosphorylation during Alzheimer’s disease

Abstract

Phosphorylation, cleavage and conformational changes in tau protein all play pivotal roles during Alzheimer's disease (AD). In an effort to determine the chronological sequence of these changes, in this study, using confocal microscopy, we compared phosphorylation at several sites (Ser(199/202/396/404/422)-Thr(205) and the second repeat domain), cleavage of tau (D(421)) and the canonical conformational Alz-50 epitope. While all of these posttranslational modifications are found in neurofibrillary tangles (NFTs) at all stages of the disease, we found significantly higher numbers of phospho-tau positive NFTs when compared with cleaved tau (P = 0.006 in Braak III; P = 0.002 in Braak IV; P = 0.012 in Braak V) or compared with the Alz-50 epitope (P < 0.05). Consistent with these findings, in a double transgenic mice model (Tet/GSK-3beta/VLW) overexpressing the enzyme glycogen synthase kinase-3beta (GSK-3beta) and tau with a triple FTDP-17 mutation (VLW) with AD-like neurodegeneration, phosphorylation at sites Ser(199/202)-Thr(205) was greater than truncated tau. Taken together, these data strongly support the notion that the conformational changes and truncation of tau occur after the phosphorylation of tau. We propose two probable pathways for the pathological processing of tau protein during AD, either phosphorylation and cleavage of tau followed by the Alz-50 conformational change or phosphorylation followed by the conformational change and cleavage as the last step.

Tau protein liquid–liquid phase separation can initiate tau aggregation

“…However, hyperphosphorylation of tau often coexists with tau aggregation in the diseased brain (Augustinack et al , 2002; Iqbal et al , 2005), but the data for a causal relationship of tau aggregation to tau phosphorylation are conflicting (Kumar et al , 2014; Tepper et al , 2014; Šimić et al , 2016). It has been reported though that tau phosphorylation, for example, by GsK3β at multiple sites, may precede the aggregation of tau in AD (Iqbal et al , 2005; Stoothoff & Johnson, 2005; Mondragón‐Rodríguez et al , 2008). And recently, Time‐Resolved ElectroSpray Ionization Mass Spectrometry (TRESI‐MS) suggested a molecular conformational shift of tau toward a more amyloidogenic structure upon phosphorylation (Zhu et al , 2015).…”

Characterization of Prefibrillar Tau Oligomers in Vitro and in Alzheimer Disease

“…The phosphorylation of serine 422 (pS 422 ) on the Tau protein is an early modification in AD pathogenesis (58,59). Thus, tissue sections from the entorhinal cortex of controls and severe AD cases were double-stained with TOC1 and pS 422 antibodies using double label immunofluorescence.…”

Effect of Curcumin and Vitamin D3 on Learning and Cognition Inrat Model of Alzheimer’s Disease

“…The decline of cholinergic transmission is also found to be associated with increased amyloid formation [5]. Similarly, tau hyperphosphorylation can be the earliest event in abnormal processing of tau protein during AD pathogenesis [6]. Hyperphosphorylated tau involves in synaptic dysfunction specifically in long-term depression (LTD) [7].…”