Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patients
Abstract Background 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 o...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-06-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13195-017-0266-6 |
| _version_ | 1819144940322553856 |
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| author | Claire Bridel Torsten Hoffmann Antje Meyer Sisi Durieux Marleen A. Koel-Simmelink Matthias Orth Philip Scheltens Inge Lues Charlotte E. Teunissen |
| author_facet | Claire Bridel Torsten Hoffmann Antje Meyer Sisi Durieux Marleen A. Koel-Simmelink Matthias Orth Philip Scheltens Inge Lues Charlotte E. Teunissen |
| author_sort | Claire Bridel |
| collection | DOAJ |
| description | Abstract Background 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 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. Methods QC 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. 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-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. Conclusions Aβ38, 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. |
| first_indexed | 2024-12-22T12:50:07Z |
| format | Article |
| id | doaj.art-57cfea3b216d464195b6f8f7c650c95a |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-12-22T12:50:07Z |
| publishDate | 2017-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-57cfea3b216d464195b6f8f7c650c95a2022-12-21T18:25:13ZengBMCAlzheimer’s Research & Therapy1758-91932017-06-019111010.1186/s13195-017-0266-6Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patientsClaire Bridel0Torsten Hoffmann1Antje Meyer2Sisi Durieux3Marleen A. Koel-Simmelink4Matthias Orth5Philip Scheltens6Inge Lues7Charlotte E. Teunissen8Neurochemistry Lab and Biobank, Department of Clinical Chemistry, VU University Medical Centre AmsterdamProbiodrug AGProbiodrug AGNeurochemistry Lab and Biobank, Department of Clinical Chemistry, VU University Medical Centre AmsterdamNeurochemistry Lab and Biobank, Department of Clinical Chemistry, VU University Medical Centre AmsterdamSwiss BioQuant AGDepartment of Neurology, Alzheimer Center, VU University Medical Centre AmsterdamProbiodrug AGNeurochemistry Lab and Biobank, Department of Clinical Chemistry, VU University Medical Centre AmsterdamAbstract Background 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 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. Methods QC 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. 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-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. Conclusions Aβ38, 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.http://link.springer.com/article/10.1186/s13195-017-0266-6Alzheimer’s diseaseCerebrospinal fluidGlutaminyl cyclaseAmyloid beta3pE-Aβ42 |
| spellingShingle | Claire Bridel Torsten Hoffmann Antje Meyer Sisi Durieux Marleen A. Koel-Simmelink Matthias Orth Philip Scheltens Inge Lues Charlotte E. Teunissen Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patients Alzheimer’s Research & Therapy Alzheimer’s disease Cerebrospinal fluid Glutaminyl cyclase Amyloid beta 3pE-Aβ42 |
| title | Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patients |
| title_full | Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patients |
| title_fullStr | Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patients |
| title_full_unstemmed | Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patients |
| title_short | Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patients |
| title_sort | glutaminyl cyclase activity correlates with levels of aβ peptides and mediators of angiogenesis in cerebrospinal fluid of alzheimer s disease patients |
| topic | Alzheimer’s disease Cerebrospinal fluid Glutaminyl cyclase Amyloid beta 3pE-Aβ42 |
| url | http://link.springer.com/article/10.1186/s13195-017-0266-6 |
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