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

Background: Pyroglutamylation of truncated A beta peptides, which is catalysed by enzyme glutaminyl cyclase (QC), generates pE-A beta species with enhanced aggregation propensities and resistance to most amino-peptidases and endo-peptidases. pE-A beta species have been identified as major constituents of A beta plaques and reduction of pE-A beta 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 beta peptides may serve as pharmacodynamic read-outs for QC inhibition. Methods: QC activity, A beta 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 beta 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 beta 38 (r = 0.83, p < 0.0001) and A beta 40 (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. Conclusions: A beta 38, A beta 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.