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

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 APP SL 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 APP SL 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).

Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems

“…First, the synthetic Aβ used here has known differences in structure, heterogeneity and toxicity compared with the Aβ found in human AD brains. Aβ isolated from AD patients comprises a complex mix of Aβ peptides with heterogeneous lengths and posttranslational modifications, 27,[56][57][58][59][60][61][62] . The use of Aβ preparations extracted from postmortem human brains using previously published extraction protocols 63 could give more insight into this hypothesis in future studies.…”

Symptomatic and Disease-Modifying Therapy Pipeline for Alzheimer’s Disease: Towards a Personalized Polypharmacology Patient-Centered Approach

“…Aβ3(pGlu)-42 is highly hydrophobic, more prone to oligomerization, and has greater resistance against proteolytic degradation. When compared with full-length Aβ forms, cortical concentrations of AβpE3 correlate more strongly with cognitive impairment and pTau and appear to be more specifically linked to the disease progression [ 53 ]. Elevated QC expression in AD tissues has been reported [ 54 ], and thus it is tempting to speculate that inhibition of QC might prevent the formation of pGlu-Aβ and suppress downstream pathophysiology [ 55 ].…”

The Hidden Role of Non-Canonical Amyloid β Isoforms in Alzheimer’s Disease

“…Unlike most Aβ variants, Aβ pyroE is only associated with the progression of AD but not with ageing [ 72 ]. In pre-clinical AD patients without senile plaque formation, Aβ pyro is not initially present within soluble aggregates [ 149 ] but appears during further progression of the disease when patients experience their first cognitive symptoms [ 149 , 153 ]. Deposition of Aβ 3-40 pyro-E3 into insoluble plaques precedes deposition of Aβ 1–42 and Aβ 1–40 [ 148 ] and may thus be involved during the onset of early symptoms.…”