The relationship between truncation and phosphorylation at the C-terminus of tau protein in the paired helical filaments of Alzheimer's disease

Abstract

We previously demonstrated that, in the early stages of tau processing in Alzheimer's disease, the N-terminal part of the molecule undergoes a characteristic cascade of phosphorylation and progressive misfolding of the proteins resulting in a structural conformation detected by Alz-50. In this immunohistochemical study of AD brain tissue, we have found that C-terminal truncation of tau at Asp-421 was an early event in tau aggregation and analyzed the relationship between phospho-dependent tau epitopes located at the C-terminus with truncation at Glu-391. The aim of this study was to determine whether C-terminal truncation may trigger events leading to the assembly of insoluble PHFs from soluble tau aggregates present in pre-tangle cells. Our findings suggest that there is a complex interaction between phosphorylated and truncated tau species. A model is presented here in which truncated tau protein represents an early neurotoxic species while phosphorylated tau species may provide a neuroprotective role in Alzheimer's disease.

Characterization of Early Pathological Tau Conformations and Phosphorylation in Chronic Traumatic Encephalopathy

“…All 3 antibodies used here (ie, pS422, TNT1, and TOC1) are markers of early, pretangle tau pathology in AD and other tauopathies (15–17, 23–26). TauC3 is an antibody (mouse IgG1, Binder/Kanaan Lab) that recognizes tau truncated at D421 (22), a modification that appears later in the early phases of NFT development and increases with progression in AD (13–16, 18–21). Astrocytes were identified using a glial fibrillary acidic protein antibody ([GFAP], mouse IgG1, G3893, Sigma, St. Louis, MO), and microglia were identified using a human leukocyte antigen–DR antibody ([HLA-DR], clone LN3, mouse IgG2b, 8693031, MP Biomed, Santa Ana, CA).…”

Presence of a carboxy-terminal pseudorepeat and disease-like pseudohyperphosphorylation critically influence tau’s interaction with microtubules in axon-like processes

“…Tau truncation appears to be an early event in AD (Reifert et al. , 2011; Flores-Rodriguez et al. , 2015) and may produce neurotoxic fragments (Park and Ferreira, 2005; Lang et al.…”

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

“…It is believed that the monomeric form fulfills the physiological functions, while soluble oligomers and/or PHFs are responsible for the neurotoxic effects. As indicated, the formation of oligomers is accompanied by increasing degrees of phosphorylation at different sites, as well as by proteolytic trimming (adapted and simplified from [13]). …”

“…Moreover, different truncated forms of the protein arising from proteolytic cleavage have been implicated in the pathological phenotypes [13,51,52]. Yet, little is known about how these modifications are provoked in a physiological context, how they affect the biological activity of the tau isoforms, and which downstream effectors are involved in mediating the cellular responses.…”