Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology
- Stephan Schilling 1, Ulrike Zeitschel , Torsten Hoffmann , Ulrich Heiser , Mike Francke , Astrid Kehlen , Max Holzer , Birgit Hutter-Paier , Manuela Prokesch , Manfred Windisch , Wolfgang Jagla , Dagmar Schlenzig , Christiane Lindner , Thomas Rudolph , Gunter Reuter , Holger Cynis , Dirk Montag , Hans-Ulrich Demuth , Steffen Rossner
- 1Probiodrug AG, Weinbergweg 22, 06120 Halle/S., Germany.
- 0Probiodrug AG, Weinbergweg 22, 06120 Halle/S., Germany.
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View abstract on PubMed
Summary
This summary is machine-generated.Pyroglutamate (pE)-amyloid-beta (Abeta) peptides initiate Alzheimer's disease pathology. Inhibiting glutaminyl cyclase reduced pE-Abeta, amyloid plaques, and improved cognitive function in animal models.
Area Of Science
- Neuroscience
- Biochemistry
- Pathology
Background
- Pyroglutamate (pE)-modified Abeta peptides are implicated in Alzheimer's disease initiation due to their aggregation and neurotoxicity.
- Glutaminyl cyclase (QC) catalyzes the N-terminal pE-formation of Abeta peptides in vivo.
Purpose Of The Study
- To investigate the role of glutaminyl cyclase in Alzheimer's disease pathogenesis.
- To evaluate the therapeutic potential of glutaminyl cyclase inhibitors in reducing pE-Abeta burden and improving cognitive deficits.
Main Methods
- Assessed glutaminyl cyclase expression in Alzheimer's disease cortices.
- Administered a glutaminyl cyclase inhibitor orally to transgenic mouse and Drosophila models of Alzheimer's disease.
- Evaluated Abeta burden, plaque formation, gliosis, and cognitive performance (context memory, spatial learning).
Main Results
- Glutaminyl cyclase expression was upregulated in Alzheimer's disease brains and correlated with pE-Abeta levels.
- Inhibitor treatment significantly reduced Abeta(3(pE)-42) burden in mouse and Drosophila models.
- Reduced Abeta plaque formation, gliosis, and improved memory and learning were observed in treated mice.
Conclusions
- Abeta(3(pE)-42) acts as a potent seed for Abeta aggregation, driving Alzheimer's disease pathology.
- Inhibition of glutaminyl cyclase effectively reduces brain pE-Abeta, offering a promising therapeutic strategy for Alzheimer's disease.
- This approach may also have implications for treating other amyloidoses, such as familial Danish dementia.
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