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

Abstract

BackgroundPyroglutamylation 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 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 Aβ peptides may serve as pharmacodynamic read-outs for QC inhibition.MethodsQC activity, Aβ 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 (Aβ42, tau and p-tau) and clinical features was evaluated.ResultsQC 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-AUCTAU = 0.878, ROC-AUCTAU&QC = 0.939 and ROC-AUCpTAU = 0.820, ROC-AUCpTAU&QC = 0.948). In AD and controls, QC activity correlates with Aβ38 (r = 0.83, p < 0.0001) and Aβ40 (r = 0.84, p < 0.0001), angiogenesis mediators (Flt1, Tie2, VEGFD, VCAM-1 and ICAM-1, r > 0.5, p < 0.0001) and core diagnostic biomarkers (r > 0.35, p = <0.0057). QC activity does not correlate with MMSE or ApoE genotype.ConclusionsAβ38, Aβ40 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-017-0266-6) contains supplementary material, which is available to authorized users.

Energy-dependent transport at dural lymphatic vessels is necessary for Aβ brain clearance in Alzheimer’s disease

“…Glutamyl cyclase (QC) is the enzyme required for conversion of N-terminal truncated Aβ isoforms to pE3-Aβ. QC levels are highly correlated with pE3-Aβ load, which is a more reliable predictor of cognitive decline using MMSE than unmodified Aβ (56,57). Of relevance to our study, prior studies have shown that QC gene expression is upregulated 16-fold in lymphatic endothelial cells (LEC) compared to blood endothelial cells (BEC) (58), but the relevance of this observation was previously unknown.…”

“…Prior studies using RNAseq to analyze gene expression data for LEC and BEC have been conducted (57,83,84). There have been some concerns that data acquired from passaged lymphatic cells may not reflect the reality of gene expression in vivo (84).…”

“…Prior work had already established that multiple ABC transporters are implicated in Aβ transport at the blood-brain barrier and CSFblood barrier (78-81), but multi-drug transporters have never been reported in meningeal lymphatic cells. However, one prior study (57) had reported at the gene expression level that multiple ABC transporters are upregulated in lymphatic endothelial cells (LEC) compared to blood endothelial cells (BEC). In particular, ABCB1 was 50-fold upregulated and ABCC3 was 12-fold upregulated.…”

The Development of Small Molecule Inhibitors of Glutaminyl Cyclase and Isoglutaminyl Cyclase for Alzheimer's Disease

“…The pE‐modification of Aβ confers unique properties, such as proteolytic resistance and loss of the N‐terminal charge, that lead to accelerated aggregation of Aβ 3(pE) compared with unmodified Aβ . Moreover, pGlu‐Aβ peptides exhibit enhanced toxicity compared to the unmodified Aβ peptide and promote the formation of tau tangles . In AD patients and animal AD models, the level and activity of QC are significantly increased .…”

“…It has been shown that the main component of senile plaques from AD patients is pE –Aβs, especially pE−Aβ 3‐40/42. In addition, some studies suggested that pGlu‐Aβ is critical to the development of AD, especially in the early stage . Therefore, QC represents an attractive target to develop novel treatments for AD .…”