Cited by 357Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer's disease–like pathology

Schilling, Stephan, Zeitschel, Ulrike, Hoffmann, Torsten, Heiser, Ulrich, Francke, Mike, Kehlen, Astrid, Holzer, Max, Hutter-Paier, Birgit +11 more·2008·Nature Medicine

Abstract

Because of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, N-terminally truncated and, in particular, pyroglutamate (pE)-modified Abeta peptides have been suggested as being important in the initiation of pathological cascades resulting in the development of Alzheimer's disease. We found that the N-terminal pE-formation is catalyzed by glutaminyl cyclase in vivo. Glutaminyl cyclase expression was upregulated in the cortices of individuals with Alzheimer's disease and correlated with the appearance of pE-modified Abeta. Oral application of a glutaminyl cyclase inhibitor resulted in reduced Abeta(3(pE)-42) burden in two different transgenic mouse models of Alzheimer's disease and in a new Drosophila model. Treatment of mice was accompanied by reductions in Abeta(x-40/42), diminished plaque formation and gliosis and improved performance in context memory and spatial learning tests. These observations are consistent with the hypothesis that Abeta(3(pE)-42) acts as a seed for Abeta aggregation by self-aggregation and co-aggregation with Abeta(1-40/42). Therefore, Abeta(3(pE)-40/42) peptides seem to represent Abeta forms with exceptional potency for disturbing neuronal function. The reduction of brain pE-Abeta by inhibition of glutaminyl cyclase offers a new therapeutic option for the treatment of Alzheimer's disease and provides implications for other amyloidoses, such as familial Danish dementia.

Integrity signals

Registry

Crossref · 10.1038/nm.1872

Cites

37 of 37 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Schilling, S., Zeitschel, U., Hoffmann, T., Heiser, U., Francke, M., Kehlen, A., Holzer, M., Hutter-Paier, B., Prokesch, M., Windisch, M., Jagla, W., Schlenzig, D., Lindner, C., Rudolph, T., Reuter, G., Cynis, H., Montag, D., Demuth, H.-U., & Rossner, S.
Affiliations
  • Probiodrug (Germany) (DE)
  • Leipzig University (DE)
  • Martin Luther University Halle-Wittenberg (DE)
  • Leibniz Institute for Neurobiology (DE)
Corresponding author
Demuth, Hans-Ulrich
Venue
Nature Medicine
Published
2008-09-28
Volume
14
Issue
10
Pages
1106-1111
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W1990632702
Cited by
357
References
37
Citations by year
2026: 10 · 2025: 15 · 2024: 15 · 2023: 13 · 2022: 15 · 2021: 25 · 2020: 15 · 2019: 15 · 2018: 23 · 2017: 16 · 2016: 20 · 2015: 23 · 2014: 32 · 2013: 27 · 2012: 26
FWCI
15.39
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
glutaminyl cyclase, pyroglutamate amyloid-beta, Alzheimer's disease, enzyme inhibition, amyloid-beta aggregation, amyloid plaques, transgenic mouse model, Drosophila model, learning and memory, gliosis, familial Danish dementia, amyloidosis, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Brain, Cells, Cultured, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors, Female, Humans, Memory, Mice, Transgenic, Pyrrolidonecarboxylic Acid, Amyloid beta-Peptides, Aminoacyltransferases, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review