Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Alzheimer's Research & Therapy
Published in: Alzheimer's Research & Therapy 1/2017

Open Access 01-12-2017 | Research

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

Authors: Claire Bridel, Torsten Hoffmann, Antje Meyer, Sisi Durieux, Marleen A. Koel-Simmelink, Matthias Orth, Philip Scheltens, Inge Lues, Charlotte E. Teunissen

Published in: Alzheimer's Research & Therapy | Issue 1/2017

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:1–14.CrossRef
2.
3.
Andrew RJ, Kellett KA, Thinakaran G, Hooper NM. A Greek Tragedy: the growing complexity of Alzheimer Amyloid precursor protein proteolysis. J Biol Chem. 2016;291(37):19235–44.
4.
Cescato R, Dumermuth E, Spiess M, Paganetti PA. Increased generation of alternatively cleaved beta-amyloid peptides in cells expressing mutants of the amyloid precursor protein defective in endocytosis. J Neurochem. 2000;74:1131–9.CrossRefPubMed
5.
Takeda K, Araki W, Akiyama H, Tabira T. Amino-truncated amyloid β-peptide (A β 5-40/42) produced from caspase-cleaved amyloid precursor protein is deposited in Alzheimer’s disease. FASEB J. 2004;18(14):1755–7.
6.
Saido TC, Yamao-Harigaya W, Iwatsubo T, Kawashima S. Amino- and carboxyl-terminal heterogeneity of beta-amyloid peptides deposited in human brain. Neurosci Lett. 1996;215:173–6.CrossRefPubMed
7.
He W, Barrow CJ. The Aβ 3-pyroglutamyl and 11-pyroglutamyl peptides found in senile plaque have greater β-sheet forming and aggregation propensities in vitro than full-length Aβ. Biochemistry. 1999;38:10871–7.CrossRefPubMed
8.
Schlenzig D, et al. Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry. 2009;48:7072–8.CrossRefPubMed
9.
Saido TC. Alzheimer’s disease as proteolytic disorders: anabolism and catabolism of beta-amyloid. Neurobiol Aging. 1998;19:S69–75.
10.
Harigaya Y, et al. Amyloid beta protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer’s disease brain. Biochem Biophys Res Commun. 2000;276:422–7.CrossRefPubMed
11.
12.
Mandler M, et al. Pyroglutamylated amyloid-β is associated with hyperphosphorylated tau and severity of Alzheimer’s disease. Acta Neuropathol. 2014;128:67–79.
13.
Wirths O, et al. Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model. Acta Neuropathol. 2009;118:487–96.CrossRefPubMedPubMedCentral
14.
15.
Cynis H, Scheel E, Saido TC, Schilling S, Demuth HU. Amyloidogenic processing of amyloid precursor protein: Evidence of a pivotal role of glutaminyl cyclase in generation of pyroglutamate-modified amyloid-β. Biochemistry. 2008;47:7405–13.
16.
Schilling S, et al. Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer’s disease-like pathology. Nat Med. 2008;14:1106–11.CrossRefPubMed
17.
Schilling S, Hoffmann T, Manhart S, Hoffmann M, Demuth HU. Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions. FEBS Lett. 2004;563:191–6.CrossRefPubMed
18.
Morawski M, et al. Glutaminyl cyclase in human cortex: correlation with (pGlu)-amyloid-β load and cognitive decline in Alzheimer’s disease. J Alzheimer’s Dis. 2014;39:385–400.
19.
Cynis H, et al. The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions. EMBO Mol Med. 2011;3:545–58.CrossRefPubMedPubMedCentral
20.
Oliveira EB, Gotschlich EC, Liu TY. Primary structure of human protein. J Bol Chem. 1979;254:489–502.
21.
Cynis H, et al. Inhibition of glutaminyl cyclases alleviates CCL2-mediated inflammation of non-alcoholic fatty liver disease in mice. Int J Exp Pathol. 2013;94:217–25.PubMedPubMedCentral
22.
Eikelenboom P, Rozemuller AJ, Hoozemans JJ, Veerhuis R, van Gool WA. Neuroinflammation and Alzheimer disease: clinical and therapeutic implications. Alzheimer Dis Assoc Disord. 2000;14 Suppl 1:S54–61.CrossRefPubMed
23.
Rubio-perez JM, Morillas-ruiz JM. A review: inflammatory process in Alzheimer’s disease, role of cytokines. Sci J. 2012;2012:756357.
24.
Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015;16:358–72.CrossRefPubMed
25.
Kauwe JSK, et al. Genome-wide association study of CSF levels of 59 Alzheimer’s disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation. PLoS Genet. 2014;10:e1004758.CrossRefPubMedPubMedCentral
26.
Sastre M, et al. Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci. 2003;23:9796–804.PubMed
27.
Yan Q, et al. Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer’s disease. J Neurosci. 2003;23:7504–9.PubMed
28.
Lues I, et al. A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects. Alzheimers Dement Transl Res Clin Interv. 2015;1:182–95.CrossRef
29.
30.
McKhann GM, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:263–9.CrossRefPubMedPubMedCentral
31.
Teunissen CE. A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking; Neurology. 2009;73(22):1914–22.
32.
Schilling S, et al. Continuous spectrometric assays for glutaminyl cyclase activity. Anal Biochem. 2002;303:49–56.CrossRefPubMed
33.
Lame ME, Chambers EE, Blatnik M. Quantitation of amyloid beta peptides Aβ(1–38), Aβ(1–40), and Aβ(1–42) in human cerebrospinal fluid by ultra-performance liquid chromatography-tandem mass spectrometry. Anal Biochem. 2011;419:133–9.CrossRefPubMed
34.
Pannee J, et al. Round robin test on quantification of amyloid-β 1–42 in cerebrospinal fluid by mass spectrometry. Alzheimers Dement. 2016;12:55–9.
35.
Kuhlmann J, et al. CSF Aβ1-42 —an excellent but complicated Alzheimer’s biomarker—a route to standardisation. Clin Chim Acta. 2017;467:27–3.
36.
Kleinschmidt M, et al. Characterizing aging, mild cognitive impairment, and dementia with blood-based biomarkers and neuropsychology. J Alzheimers Dis. 2015;50:111–26.CrossRef
37.
De Kimpe L, et al. Disturbed Ca2+ homeostasis increases glutaminyl cyclase expression; connecting two early pathogenic events in Alzheimer’s disease in vitro. PLoS One. 2012;7:e44674.CrossRefPubMedPubMedCentral
38.
Valenti MT, et al. Increased glutaminyl cyclase expression in peripheral blood of Alzheimer’s disease patients. J Alzheimers Dis. 2013;34:263–71.PubMed
39.
Baldeiras I, et al. Cerebrospinal fluid Aβ40 is similarly reduced in patients with frontotemporal lobar degeneration and Alzheimer’s disease. J Neurol Sci. 2015;358:308–16.
40.
Dorey A, Perret-Liaudet A, Tholance Y, Fourier A, Quadrio I. Cerebrospinal fluid Aβ40 improves the interpretation of Aβ42 concentration for diagnosing Alzheimer’s disease. Front Neurol. 2015;6:1–7.CrossRef
41.
Lewczuk P, et al. Cerebrospinal fluid Aβ42/40 corresponds better than Aβ42 to amyloid PET in Alzheimer’s disease.  J Alzheimers Dis. 2017;55(2):813–22.
42.
Lewczuk P, et al. Neurochemical diagnosis of Alzheimer’s dementia by CSF Aβ42, Aβ42/Aβ40 ratio and total tau. Neurobiol Aging. 2004;25:273–81.CrossRefPubMed
43.
44.
Kim HJ, et al. Elevation of the plasma Aβ40-Aβ42 ratio as a diagnostic marker of sporadic early-onset Alzheimer’s disease. J Alzheimers Dis. 2015;48(4):1043–50.CrossRefPubMed
45.
Blennow K, et al. Evolution of Abeta42 and Abeta40 levels and Abeta42-Abeta40 ratio in plasma during progression of Alzheimer’s disease, a multicenter assessment. J Nutr Health Aging. 2009;13(3):205–8.CrossRefPubMed
46.
Abraham J-D, et al. Cerebrospinal Aβ11-x and 17-x levels as indicators of mild cognitive impairment and patients’ stratification in Alzheimer's disease. Transl Psychiatry. 2013;3:e281.CrossRefPubMedPubMedCentral
47.
Del Bo R, Ghezzi S, Scarpini E, Bresolin N, Comi GP. VEGF genetic variability is associated with increased risk of developing Alzheimer’s disease. J Neurol Sci. 2009;283:66–8.CrossRefPubMed
48.
Chiappelli M, et al. VEGF gene and phenotype relation with Alzheimer’s disease and mild cognitive impairment. Rejuvenation Res. 2006;9:485–93.CrossRefPubMed
49.
Patel NS, et al. Alzheimer’s β-amyloid peptide blocks vascular endothelial growth factor mediated signaling via direct interaction with VEGFR-2. J Neurochem. 2010;112:66–76.
50.
51.
Wang P, et al. VEGF-induced angiogenesis ameliorates the memory impairment in APP transgenic mouse model of Alzheimer’s disease. Biochem Biophys Res Commun. 2011;411:620–6.CrossRefPubMed
52.
Herran E, et al. Enhanced hippocampal neurogenesis in APP-Ps1 mouse model of Alzheimer’s disease after implantation of VEGF-loaded PLGA nanospheres. Curr Alzheimer Res. 2015;12(10):932–40.CrossRefPubMed
53.
Yu S, et al. Diagnostic utility of VEGF and soluble CD40L levels in serum of Alzheimer’s patients. Clin Chim Acta. 2016;453:154–9.CrossRefPubMed
54.
Huang L, Jia J, Liu R. Decreased serum levels of the angiogenic factors VEGF and TGF-β1 in Alzheimer’s disease and amnestic mild cognitive impairment. Neurosci Lett. 2013;550:60–3.
55.
Mateo I, et al. Low serum VEGF levels are associated with Alzheimer’s disease. Acta Neurol Scand. 2007;116:56–8.CrossRefPubMed
56.
Tarkowski E, et al. Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer’s disease and vascular dementia. Neurobiol Aging. 2002;23:237–43.CrossRefPubMed
Metadata
Title
Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patients
Authors
Claire Bridel
Torsten Hoffmann
Antje Meyer
Sisi Durieux
Marleen A. Koel-Simmelink
Matthias Orth
Philip Scheltens
Inge Lues
Charlotte E. Teunissen
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 1/2017
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/s13195-017-0266-6

Other articles of this Issue 1/2017

Alzheimer's Research & Therapy 1/2017 Go to the issue

Research

The effects of different familial Alzheimer’s disease mutations on APP processing in vivo

Research

Anemia is associated with incidence of dementia: a national health screening study in Korea involving 37,900 persons

Research

Increased dementia risk predominantly in diabetes mellitus rather than in hypertension or hyperlipidemia: a population-based cohort study

Research

Cognitive and imaging markers in non-demented subjects attending a memory clinic: study design and baseline findings of the MEMENTO cohort

Research

Comparison of CSF markers and semi-quantitative amyloid PET in Alzheimer’s disease diagnosis and in cognitive impairment prognosis using the ADNI-2 database

Research

ERβ and ApoE isoforms interact to regulate BDNF–5-HT2A signaling and synaptic function in the female brain