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.
Highlights
Pyroglutamylation of truncated Amyloid beta (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)
Pyroglutamylation of truncated Aβ species carrying a glutamate residue at position 3 or 11 is catalysed by enzyme glutaminyl cyclase (QC) [15,16,17], whose expression is increased in temporal and enthorinal cortices of AD patients and correlates with insoluble pE-Aβ aggregates [18]
In addition to N-terminal glutamate Aβ species, Glutaminyl cyclase (QC) catalyses pyroglutamation of a number of other substrates harbouring an N-terminal glutamine residue, including inflammatory mediators monocyte chemoattractant proteins (MCP) 1–4 [19] and possibly fractalkine (CX3CL1) (Kehlen et al, manuscript in preparation), C-reactive protein (CRP) [20] and soluble ICAM-1 [19, 21]. These may be of particular relevance to AD pathomechanisms, because local chronic inflammation resulting from microglia and astrocyte activation by Aβ aggregates is a well-described feature of AD pathology [22,23,24] and affects amyloid precursor protein (APP) and Aβ processing [25,26,27]
Summary
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). In addition to N-terminal glutamate Aβ species, QC catalyses pyroglutamation of a number of other substrates harbouring an N-terminal glutamine residue, including inflammatory mediators monocyte chemoattractant proteins (MCP) 1–4 ( known as CCL2, CCL8, CCL7 and CCL13) [19] and possibly fractalkine (CX3CL1) (Kehlen et al, manuscript in preparation), C-reactive protein (CRP) [20] and soluble ICAM-1 [19, 21] These may be of particular relevance to AD pathomechanisms, because local chronic inflammation resulting from microglia and astrocyte activation by Aβ aggregates is a well-described feature of AD pathology [22,23,24] and affects APP and Aβ processing [25,26,27]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
