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

• Published in: Alzheimer's research & therapy 2017-06, Vol.9 (1)
• Main Authors: Bridel, Claire, Hoffmann, Torsten, Meyer, Antje, Durieux, Sisi, Koel-Simmelink, Marleen A, Orth, Matthias, Scheltens, Philip, Lues, Inge, Teunissen, Charlotte E
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid beta-protein; Care and treatment; Cerebrospinal fluid; Development and progression; Genetic aspects; Health aspects; Neovascularization
• ISSN: 1758-9193; 1758-9193
• DOI: 10.1186/s13195-017-0266-6

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.sub.TAU = 0.878, ROC-AUC.sub.TAU&.sub.QC = 0.939 and ROC-AUC.sub.pTAU = 0.820, ROC-AUC.sub.pTAU&.sub.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 =