Dataset Information

Glutaminyl cyclase activity correlates with levels of A? peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer's disease patients.

ABSTRACT:

Background

Pyroglutamylation of truncated A? peptides, which is catalysed by enzyme glutaminyl cyclase (QC), generates pE-A? species with enhanced aggregation propensities and resistance to most amino-peptidases and endo-peptidases. pE-A? species have been identified as major constituents of A? plaques and reduction of pE-A? species is associated with improvement of cognitive tasks in animal models of Alzheimer's disease (AD). Pharmacological inhibition of QC has thus emerged as a promising therapeutic approach for AD. Here, we question whether cerebrospinal fluid (CSF) QC enzymatic activity differs between AD patients and controls and whether inflammatory or angiogenesis mediators, some of which are potential QC substrates, and/or A? peptides may serve as pharmacodynamic read-outs for QC inhibition.

Methods

QC activity, A? peptides and inflammatory or angiogenesis mediators were measured in CSF of a clinically well-characterized cohort of 20 mild AD patients, 20 moderate AD patients and 20 subjective memory complaints (SMC) controls. Correlation of these parameters with core diagnostic CSF AD biomarkers (A?42, tau and p-tau) and clinical features was evaluated.

Results

QC activity shows a tendency to decrease with AD progression (p?=?0.129). The addition of QC activity to biomarkers tau and p-tau significantly increases diagnostic power (ROC-AUC_TAU?=?0.878, ROC-AUC_TAU&_QC?=?0.939 and ROC-AUC_pTAU?=?0.820, ROC-AUC_pTAU&_QC?=?0.948). In AD and controls, QC activity correlates with A?38 (r?=?0.83, p??0.5, p??0.35, p?=?<0.0057). QC activity does not correlate with MMSE or ApoE genotype.

Conclusions

A?38, A?40 and angiogenesis mediators (Flt1, Tie2, VEGFD, VCAM-1 and ICAM-1) are potential pharmacodynamic markers of QC inhibition, because their levels closely correlate with QC activity in AD patients. The addition of QC activity to core diagnostic CSF biomarkers may be of specific interest in clinical cases with discordant imaging and biochemical biomarker results.

SUBMITTER: Bridel C

PROVIDER: S-EPMC5461753 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer's disease patients.

Bridel Claire C Hoffmann Torsten T Meyer Antje A Durieux Sisi S Koel-Simmelink Marleen A MA Orth Matthias M Scheltens Philip P Lues Inge I Teunissen Charlotte E CE

Alzheimer's research & therapy 20170606 1

<h4>Background</h4>Pyroglutamylation of truncated Aβ peptides, which is catalysed by enzyme glutaminyl cyclase (QC), generates pE-Aβ species with enhanced aggregation propensities and resistance to most amino-peptidases and endo-peptidases. pE-Aβ species have been identified as major constituents of Aβ plaques and reduction of pE-Aβ species is associated with improvement of cognitive tasks in animal models of Alzheimer's disease (AD). Pharmacological inhibition of QC has thus emerged as a promis ...[more]

PMID: 28587659

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