Correlation of pyroglutamate amyloid β and ptau Ser202/Thr205 levels in Alzheimer's disease and related murine models.

Joerg Neddens,Stefanie Flunkert,Lauren Walker,Kerstin Beutl,Tina Loeffler,Magdalena Daurer,Johannes Attems,Birgit Hutter-Paier,Stephen D Ginsberg

doi:10.1371/journal.pone.0235543

Abstract

Senile plaques frequently contain Aβ-pE(3), a N-terminally truncated Aβ species that is more closely linked to AD compared to other Aβ species. Tau protein is highly phosphorylated at several residues in AD, and specifically phosphorylation at Ser202/Thr205 is known to be increased in AD. Several studies suggest that formation of plaques and tau phosphorylation might be linked to each other. To evaluate if Aβ-pE(3) and ptau Ser202/Thr205 levels correlate in human and transgenic AD mouse models, we analyzed human cortical and hippocampal brain tissue of different Braak stages as well as murine brain tissue of two transgenic mouse models for levels of Aβ-pE(3) and ptau Ser202/Thr205 and correlated the data. Our results show that Aβ-pE(3) formation is increased at early Braak stages while ptau Ser202/Thr205 mostly increases at later stages. Further analyses revealed strongest correlations between the two pathologies in the temporal, frontal, cingulate, and occipital cortex, however correlation in the hippocampus was weaker. Evaluation of murine transgenic brain tissue demonstrated a slow but steady increase of Aβ-pE(3) from 6 to 12 months of age in the cortex and hippocampus of APPSL mice, and a very early and strong Aβ-pE(3) increase in 5xFAD mice. ptau Ser202/Thr205 levels increased at the age of 9 months in APPSL mice and at 6 months in 5xFAD mice. Our results show that Aβ-pE(3) and ptau Ser202/Thr205 levels strongly correlate in human as well as murine tissues, suggesting that tau phosphorylation might be amplified by Aβ-pE(3).

Highlights

Alzheimer’s disease (AD) is characterized by two major pathologies, aggregated tau and amyloid β (Aβ) plaques.Tau pathology manifests as neurofibrillary tangles and neuropil threads, and strongly depends on posttranslational modifications of tau
We investigated 5 neuroanatomical regions, which partly reflect the topographical spreading of tau pathology according to Braak stages: hippocampus (HC), temporal cortex (TeCtx), cingulate cortex (CiCtx), occipital cortex (OcCtx), and frontal cortex (FrCtx)
To evaluate the specificity of two Aβ-pE(3) antibodies, different labeling was performed in human frontal cortical tissue of cases that were Braak stage V/VI, as well as cortical and hippocampal tissue of AD mouse models

Summary

Introduction

Alzheimer’s disease (AD) is characterized by two major pathologies, aggregated tau and amyloid β (Aβ) plaques. Tau pathology manifests as neurofibrillary tangles and neuropil threads, and strongly depends on posttranslational modifications of tau. Phosphorylation at different residues has been evaluated in detail (for review see [1]). Correlation of Aβ-pE(3) and ptau in human and mouse the manuscript. QPS Austria GmbH provided support in the form of salaries of JN, MD, SF, TL and BHP. As QPS employees, these authors had main roles in the study design, data collection and analysis, decision to publish, and preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section

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Conclusion