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.
Highlights
Tau pathology, a principal hallmark of Alzheimer’s disease, is characterized by abnormal hyperphosphorylation and truncation of tau proteins (Wischik et al, 1988a; Goedert et al, 1992; Novak et al, 1993; Mena et al, 1996)
The aim of this study was to determine whether C-terminal truncation may trigger events leading to the assembly of insoluble paired helical filaments (PHFs) from soluble tau aggregates present in pre-tangle cells
DOUBLE IMMUNOLABELING WITH TauC3 AND pS396 IN neurofibrillary tangles (NFTs) Truncation at Asp-421, detected using monoclonal antibody (mAb) TauC3, is an early event in tau processing in pre-tangle cells (Rissman et al, 2004; Luna-Munoz et al, 2007; Mena and Luna-muñoz, 2009)
Summary
A principal hallmark of Alzheimer’s disease, is characterized by abnormal hyperphosphorylation and truncation of tau proteins (Wischik et al, 1988a; Goedert et al, 1992; Novak et al, 1993; Mena et al, 1996). While sarkosyl-soluble PHFs are mainly constituted of tau protein in a hyperphosphorylated state, insoluble PHF fractions from Alzheimer’s disease brains are Pronase resistant and phosphorylated tau accounts for no more than 15% of the content of such PHFs (Wischik et al, 1995). Rather than promoting the aggregation of tau, phosphorylation of tau is inhibitory for aggregation in vitro (Schneider et al, 1999)
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