Article
Biochemistry & Molecular Biology
Adam P. Gunn, Bruce X. Wong, Catriona McLean, Chris Fowler, Peter J. Barnard, James A. Duce, Blaine R. Roberts
Summary: QC expression is elevated in the brain tissues of AD individuals, with a modest increase in sQC protein and enzyme activity. Plasma QC activity did not show significant differences between the AD and control groups, but a slight increase was observed in female AD individuals. Plasma QC activity was correlated with levels of circulating monocytes in AD individuals, indicating an association with AD pathology.
JOURNAL OF NEUROCHEMISTRY
(2021)
Review
Geriatrics & Gerontology
Daoyuan Chen, Qingxiu Chen, Xiaofei Qin, Peipei Tong, Liping Peng, Tao Zhang, Chunli Xia
Summary: Human glutaminyl cyclase (hQC) has gained attention as a potential target for Alzheimer's disease (AD) due to its involvement in the pathology of AD. A recent study showed promising results with a competitive QC inhibitor, PQ912, highlighting its potential as a treatment for AD. This review discusses the discovery and evolution of hQC inhibitors, focusing on recent reports of classic Zinc binding group (ZBG)-containing chemicals, and explores the development of QC inhibitors as a promising therapy for AD.
FRONTIERS IN AGING NEUROSCIENCE
(2023)
Article
Chemistry, Medicinal
Nguyen Van Manh, Van-Hai Hoang, Van T. H. Ngo, Jihyae Ann, Tae-Ho Jang, Jung-Hye Ha, Jae Young Song, Hee-Jin Ha, Hee Kim, Young-Ho Kim, Jiyoun Lee, Jeewoo Lee
Summary: Inhibition of glutaminyl cyclase (QC) shows promise in treating early Alzheimer's disease by reducing toxic beta-amyloid in patients' brains. Among the tested compounds, one derivative (227) exhibited strong in vivo efficacy and may provide a potential therapeutic option for early-stage AD treatment. This study suggests small molecule-based QC inhibitors could be a viable approach for AD therapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Yidan Zhang, Yifan Wang, Zhan Zhao, Weixun Peng, Peng Wang, Ximing Xu, Chenyang Zhao
Summary: Glutaminyl cyclases (QC) are enzymes that protect proteins and increase their stability by catalyzing the cyclization of proteins. Aberrant N-terminal pyroglutamate, which is catalyzed by QC, has been found in various diseases. Human QC includes sQC and gQC, and their substrates are associated with neurodegenerative diseases and cancers. QC inhibitors, such as PQ912, have been developed and studied for the treatment of AD.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2022)
Article
Neurosciences
Guido Domingo, Luisa Benussi, Claudia Saraceno, Michela Bertuzzi, Roland Nicsanu, Antonio Longobardi, Sonia Bellini, Alfredo Cagnotto, Mario Salmona, Giuliano Binetti, Roberta Ghidoni
Summary: A newly developed antibody-free method was used to identify and quantify Aβ isoforms in human CSF, revealing the presence of novel Aβ species. Among these, five Aβ isoforms found in CSF of elderly individuals may serve as potential markers for Alzheimer's disease progression.
FRONTIERS IN NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Torsten Hoffmann, Jens-Ulrich Rahfeld, Mathias Schenk, Falk Ponath, Koki Makioka, Birgit Hutter-Paier, Inge Lues, Cynthia A. Lemere, Stephan Schilling
Summary: The combination therapy of Varoglutamstat and a pGlu3-Aβ-specific antibody resulted in a significant reduction of Aβ levels in transgenic mice, with an additive effect of the compounds. While PQ912 prevents the formation of pGlu3-Aβ, the antibody clears existing pGlu3-Aβ deposits, suggesting a potential for reducing individual compound doses while maintaining therapeutic effects.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Anne-Cathrine S. Vogt, Gary T. Jennings, Mona O. Mohsen, Monique Vogel, Martin F. Bachmann
Summary: Alzheimer's disease is the most common form of dementia and is responsible for 60-70% of cases. The number of people with dementia is expected to triple by 2050 due to an aging population. Currently, there are only symptomatic treatments available, making it crucial to develop novel therapeutic strategies to prevent or delay the onset of Alzheimer's disease. This mini-review focuses on the understanding of Alzheimer's disease pathobiology and discusses current immunomodulating therapies targeting amyloid-beta protein.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Clinical Neurology
Ting-Bin Chen, Kun-Ju Lin, Szu-Ying Lin, Yi-Jung Lee, Yi-Cheng Lin, Chen-Yu Wang, Jun-Peng Chen, Pei-Ning Wang
Summary: The study explored the potential associations of plasma A beta(pE) and total tau (t-tau) with brain A beta burden and cognitive performance. The results showed that plasma A beta(pE3-40)/t-tau ratios correlated with cognitive function and cerebral A beta burden, indicating its potential as a candidate clinical biomarker for AD pathology. Further examination in larger studies is warranted.
FRONTIERS IN NEUROLOGY
(2021)
Article
Biochemistry & Molecular Biology
Keng-Chang Tsai, Yi-Xuan Zhang, Hsiang-Yun Kao, Kit-Man Fung, Tien-Sheng Tseng
Summary: Alzheimer's disease (AD) is a rapidly growing condition in the elderly population and poses a significant burden on public health, society, and the global economy. In this study, we identified potential inhibitors of human glutaminyl cyclase (hQC), an essential target for developing anti-AD therapeutics, from natural products. Two compounds, Azaleatin and Quercetin, showed strong inhibitory potency against hQC and demonstrated bioactive potential in the treatment of AD. Surface plasmon resonance (SPR) and molecular modeling/simulations were employed to analyze the binding affinity and molecular interactions of these compounds.
Article
Biochemistry & Molecular Biology
Ashwani Kumar, Kiran Bagri, Manisha Nimbhal, Parvin Kumar
Summary: Alzheimer's disease is a common neurodegenerative disorder that poses an economic burden on developing countries. Research suggests that the use of Glutaminyl cyclase inhibitors can efficiently improve symptoms of the disease. The efficiency of Monte Carlo based QSAR modelling studies on a dataset of inhibitors shows promising results.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2021)
Article
Biochemistry & Molecular Biology
K. Dileep, Naoki Sakai, Kentaro Ihara, Miyuki Kato-Murayama, Akiko Nakata, Akihiro Ito, D. M. Sivaraman, Jay W. Shin, Minoru Yoshida, Mikako Shirouzu, Kam Y. J. Zhang
Summary: Alzheimer's disease is a major public health concern with limited therapeutic options. Inhibiting sQC to prevent the formation of neurotoxic pGlu-Aβ offers a promising disease-modifying therapy for AD. A novel sQC inhibitor, Cpd-41, was identified with unique binding mode and moderate toxicity, making it a potential candidate for designing high affinity sQC inhibitors.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Chemistry, Medicinal
Chenshu Xu, Yi-nan Wang, Haiqiang Wu
Summary: The paragraph discusses the importance of pyroglutamate (pE) modification catalyzed by glutaminyl cyclase (QC) in mammals, particularly in humans, and its significant role in diseases. Upregulation of QC is associated with various diseases, making it a reasonable target for therapeutic development.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Judite R. M. Coimbra, Paula I. Moreira, Armanda E. Santos, Jorge A. R. Salvador
Summary: This review explores the biological functions and structures of QPCT/L enzymes, highlights their therapeutic relevance, and summarizes recent developments in the discovery of small-molecule inhibitors targeting these enzymes.
DRUG DISCOVERY TODAY
(2023)
Article
Chemistry, Multidisciplinary
Tao Sun, Qiaoqiao Shi, Yongzhi Zhang, Chanikarn Power, Camilla Hoesch, Shawna Antonelli, Maren K. Schroeder, Barbara J. Caldarone, Nadine Taudte, Mathias Schenk, Thore Hettmann, Stephan Schilling, Nathan J. McDannold, Cynthia A. Lemere
Summary: The use of focused ultrasound (FUS) with microbubbles enhanced the delivery of an Fc-competent anti-pGlu3 Aβ monoclonal antibody to the brain, resulting in improved cognitive function and reduced plaque burden in aged Alzheimer's disease-like model mice. Additionally, the combination of antibody treatment with FUS-BBBD led to greater monocyte infiltration to plaques, suggesting a potential novel mechanism for enhancing immunotherapy efficacy in Alzheimer's disease.
JOURNAL OF CONTROLLED RELEASE
(2021)
Article
Neurosciences
Valentina Latina, Giacomo Giacovazzo, Federica Cordella, Bijorn Omar Balzamino, Alessandra Micera, Monica Varano, Cristina Marchetti, Francesca Malerba, Rita Florio, Bruno Bruni Ercole, Federico La Regina, Anna Atlante, Roberto Coccurello, Silvia Di Angelantonio, Pietro Calissano, Giuseppina Amadoro
Summary: The retina and optic nerve are sites of extra-cerebral manifestations of Alzheimer's Disease, with tau protein truncation leading to pathological changes and administration of the specific 12A12mAb showing beneficial effects on ocular injury. This research opens new avenues for the clinical management of cerebral and extracerebral AD signs by targeting tau protein modifications and their neuroprotective actions.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2021)
