Article
Biochemistry & Molecular Biology
Dieter Petit, Manuel Hitzenberger, Matthias Koch, Sam Lismont, Katarzyna Marta Zoltowska, Thomas Enzlein, Carsten Hopf, Martin Zacharias, Lucia Chavez-Gutierrez
Summary: This study investigates the interactions between an imidazole-based GSM and its target gamma-secretase-APP, and reveals that a part of the modulator interacts with a binding site on gamma-secretase, triggering rearrangements and stabilizing enzyme-substrate interactions.
Review
Neurosciences
Gunnar Nordvall, Johan Lundkvist, Johan Sandin
Summary: Recent clinical data have shown that removing A beta-amyloid plaques in early Alzheimer's disease can slow down disease progression. This progress validates the amyloid cascade hypothesis and highlights the importance of targeting A beta-amyloid for therapeutic purposes. It also suggests that reducing the production of amyloidogenic A beta can prevent the formation of A beta-pathology. Further research is needed to explore the potential of gamma-secretase modulators in preventing and treating Alzheimer's disease.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Matthias Koch, Thomas Enzlein, Shu-Yu Chen, Dieter Petit, Sam Lismont, Martin Zacharias, Carsten Hopf, Lucia Chavez-Gutierrez
Summary: This study explores the mechanism that controls the processing of the amyloid precursor protein (APP) by gamma-secretases, which is crucial in determining the length of amyloid-beta (A beta) peptides and their role in Alzheimer's disease (AD) pathogenesis. The researchers found that polar interactions established by the APPC99 ectodomain (ECD) play a key role in regulating the cleavage of APP by gamma-secretases. Increasing the hydrophobicity of APPC99-ECD attenuates substrate-driven product release and rescues the effects of Alzheimer's disease-associated pathogenic gamma-secretase and APP variants on A beta length. Furthermore, the study reveals that APPC99-ECD facilitates the production of longer A beta peptides caused by certain gamma-secretase inhibitors. These findings highlight the importance of the APPC99-ECD in regulating gamma-secretase activity and suggest it as a potential target for developing compounds that can selectively promote APP processing by these enzymes.
Review
Chemistry, Medicinal
Weimin Qiu, Hui Liu, Yijun Liu, Xin Lu, Lei Wang, Yanyu Hu, Feng Feng, Qi Li, Haopeng Sun
Summary: Alzheimer's disease (AD) is a difficult to treat progressive neurodegenerative disease characterized by the accumulation of amyloid beta (A beta) plaques in the brain. A beta interacts with various receptors on the plasma membrane and mediates signaling pathways that contribute to the development of AD. Despite ongoing research, there are currently no effective medications for AD. This review discusses the importance of A beta in the pathogenesis of AD, recent progress in targeting A beta-related receptors and compounds, and the challenges and opportunities in developing effective therapies for AD.
MEDICINAL RESEARCH REVIEWS
(2023)
Review
Biochemistry & Molecular Biology
Lucia Gallego Villarejo, Lisa Bachmann, David Marks, Maite Brachthaeuser, Alexander Geidies, Thorsten Mueller
Summary: Intracellular amyloid beta (iAβ) plays a crucial role in neurodegeneration and serves as a pathological marker. Modulating iAβ through pharmacological treatment has shown beneficial effects on cognitive properties. Future research should focus on the impact of viral infections on iAβ generation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Physical
Fatih Tok, Begum Nurpelin Saglik, Yusuf Ozkay, Zafer Asim Kaplancikli, Bedia Kocyigit-Kaymakcioglu
Summary: A new series of 6-chloro-N'-(substituted benzylidene)nicotinohydrazide compounds were synthesized and evaluated for their enzyme inhibitory activity and plaque inhibitory potency. Compound P5 showed significant activity, particularly against AChE and BACE-1, and demonstrated high blood-brain barrier permeation.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Biochemistry & Molecular Biology
Hikari Watanabe, Chika Yoshida, Masafumi Hidaka, Tomohisa Ogawa, Taisuke Tomita, Eugene Futai
Summary: Through studying Aph1 mutations and using a yeast gamma-secretase assay, we found that the L30F/T164A mutation can activate gamma-secretase activity, leading to increased production of Aβ in mouse embryonic fibroblasts without apparent modulatory function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Pharmacology & Pharmacy
Bruno P. Imbimbo, Stefania Ippati, Mark Watling, Camillo Imbimbo
Summary: According to the beta-amyloid (A beta) hypothesis, brain A beta accumulation is the primary cause of cognitive deficit and dementia in Alzheimer's disease (AD). While many anti-A beta drugs have failed in clinical trials, recent studies have shown encouraging results for antibodies that clear amyloid plaques. These findings suggest that decreased levels of soluble monomeric A beta may be the main driver of AD, rather than the aggregated forms.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Ryota Suzuki, Haruka Takahashi, Chika Yoshida, Masafumi Hidaka, Tomohisa Ogawa, Eugene Futai
Summary: In this study, the APP mutation T714I, which is associated with familial Alzheimer's disease, was found to severely reduce the cleavage of A beta. Secondary mutations were identified that restored the cleavage of APP T714I and could modulate the production of A beta species in mammalian cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Neurosciences
Yee Jie Yeap, Nagaendran Kandiah, Dean Nizetic, Kah-Leong Lim
Summary: Alzheimer's disease (AD) is the most common cause of dementia, affecting millions of elderly individuals worldwide. Despite extensive research, the cause of AD remains controversial and there is currently no cure. However, recent studies have identified the protease BACE2 as a potential therapeutic target for AD due to its non-amyloidogenic role in preventing the generation of toxic amyloid-beta peptides. This review discusses emerging evidence supporting the neuroprotective role of BACE2 in AD and provides an update on the identification of gene mutations linked to increased risk and earlier disease onset.
JOURNAL OF ALZHEIMERS DISEASE
(2023)
Article
Multidisciplinary Sciences
Chen Jin, Jiaoni Wang, Yumeng Wang, Bojun Jia, Xuefei Guo, Guanghui Yang, Peng Xu, Paul Greengard, Rui Zhou, Yigong Shi
Summary: In this study, researchers discovered that GSAP-16K can modulate the cleavage of APP by gamma-secretase through both dilute phase and condensate formation. The dilute phase of GSAP-16K promotes the production of Aβ42, while the condensates of GSAP-16K reduce the cleavage of APP-C99. Additionally, GSAP-16K stably associates with APP-C99 through specific sequence elements. These findings provide mechanistic insights into the modulation of gamma-secretase activity and have implications for the development of potential therapeutics for diseases like Alzheimer's disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Neurosciences
Yan Tan, Jiani Zhang, Ke Yang, Zihui Xu, Huawei Zhang, Weihang Chen, Tiantian Peng, Xu Wang, Zhaoheng Liu, Peng Wei, Na Li, Zhenqiang Zhang, Tonghua Liu, Qian Hua
Summary: This study found that these four anti-stroke CHMs regulate A beta PP processing through different mechanisms, with T2 being a promising candidate for AD treatment.
JOURNAL OF ALZHEIMERS DISEASE
(2022)
Article
Neurosciences
Ye-Ran Wang, Meng-Ting Wang, Xiao-Qin Zeng, Yu-Hui Liu, Yan-Jiang Wang
Summary: This study found lower plasma levels of NAbs-PS1 in AD patients, which were negatively associated with brain A beta load and positively associated with cognitive functions. Plasma NAbs-PS1 could be potential biomarkers for distinguishing AD patients from non-AD cognitive impairment subjects.
JOURNAL OF ALZHEIMERS DISEASE
(2022)
Article
Neurosciences
Lauren Owens, Joshua Bracewell, Alexandre Benedetto, Neil Dawson, Christopher Gaffney, Edward Parkin
Summary: In this study, the depletion of sA beta PP alpha and the accumulation of sA beta PP alpha' were found to contribute to cytotoxicity in AD-related neuroblastoma cells overexpressing BACE1. These findings provide new insights into the pathological mechanisms of AD and raise questions about previous studies using 6E10 antibody as a biomarker.
JOURNAL OF ALZHEIMERS DISEASE
(2022)
Article
Clinical Neurology
Yaqi Wang, Yuting Cui, Jing Liu, Qiao Song, Min Cao, Yuli Hou, Xiaomin Zhang, Peichang Wang
Summary: The upregulation of KLF5 is found to positively regulate BACE1 and accelerate APP amyloidogenic cleavage in Alzheimer's disease (AD) progression. The levels of KLF5 significantly increase in AD patients and APP/PS1 mice, and are closely related to cognitive capacity. KLF5 promotes amyloidogenic metabolism and AP synthesis through BACE1.
ALZHEIMERS RESEARCH & THERAPY
(2022)
Article
Biology
Jonas Cordes, Thomas Enzlein, Christian Marsching, Marven Hinze, Sandy Engelhardt, Carsten Hopf, Ivo Wolf
Summary: M(2)aia is an extensible open-source application that provides interactive and memory-efficient data access and signal processing for multiple large MSI datasets. It extends MITK and offers features such as fast visual interaction, image segmentation, 3D image reconstruction, and multi-modal registration, making it suitable for a wide range of MSI analysis tasks.
Article
Multidisciplinary Sciences
Wojciech Michno, Katie M. Stringer, Thomas Enzlein, Melissa K. Passarelli, Stephane Escrig, Karina Vitanova, Jack Wood, Kaj Blennow, Henrik Zetterberg, Anders Meibom, Carsten Hopf, Frances A. Edwards, Jorg Hanrieder
Summary: The study used metabolic isotope labeling and mass spectrometry imaging techniques to monitor the earliest seeds of Aβ plaque formation and revealed the aggregation dynamics of different Aβ species within plaques. It was found that the formation of structurally distinct plaques is associated with differential Aβ peptide deposition, with Aβ 1-42 forming an initial core structure followed by radial outgrowth and late secretion and deposition of Aβ 1-38.
Article
Biochemistry & Molecular Biology
Wojciech Michno, Patrick M. Wehrli, Srinivas Koutarapu, Christian Marsching, Karolina Minta, Junyue Ge, Sven W. Meyer, Henrik Zetterberg, Kaj Blennow, Corinna Henkel, Janina Oetjen, Carsten Hopf, Jorg Hanrieder
Summary: This study utilized advanced chemical imaging tools to investigate the role of neuronal lipids in the pathophysiology of Alzheimer's disease, revealing the association between lipidomic microenvironment and structural polymorphism of Aβ plaques. The research also identified lipid patterns enriched and depleted at plaques, demonstrating the potential of multimodal imaging approaches to overcome limitations associated with conventional advanced MS imaging applications.
JOURNAL OF NEUROCHEMISTRY
(2022)
Article
Biochemical Research Methods
Melissa S. Unger, Martina Blank, Thomas Enzlein, Carsten Hopf
Summary: Cell-based assays for compound screening and profiling are crucial in life sciences, chemical biology, and pharmaceutical research, and label-free technologies using MALDI-TOF mass spectrometry offer speed, sensitivity, accuracy, and versatility in drug research. This protocol outlines the development, optimization, and validation of MALDI-TOF MS cell assays to measure transporter substrate uptake, monitor drug target engagement, or discover drug-response markers.
Article
Multidisciplinary Sciences
Martina Blank, Thomas Enzlein, Carsten Hopf
Summary: This study used matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to investigate the lipid patterns in activated microglial cells. The results showed significant differences in lipid profiles between lipopolysaccharide (LPS)-stimulated and unstimulated cells, leading to the identification of 21 potential inflammation-associated lipid markers. Additionally, treatment with a histone deacetylase inhibitor reduced the inflammation response in LPS-stimulated microglial cells.
SCIENTIFIC REPORTS
(2022)
Review
Biochemistry & Molecular Biology
Kathrin M. Engel, Patricia Prabutzki, Jenny Leopold, Ariane Nimptsch, Katharina Lemmnitzer, D. R. Naomi Vos, Carsten Hopf, Juergen Schiller
Summary: Matrix-assisted laser desorption and ionization (MALDI) mass spectrometry (MS) is a valuable tool in lipid research due to its speed, sensitivity, and ability to tolerate impurities. This article discusses the methodology, ion-forming processes, and characteristics of different lipid classes in MALDI MS, with a focus on glycerophospholipids. The article also highlights the progress made in the last decade, particularly in the quantitative aspects of MALDI MS. The careful choice of matrix and the combination of MALDI MS with thin-layer chromatography (TLC) are emphasized as important factors for successful lipid detection.
PROGRESS IN LIPID RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Dieter Petit, Manuel Hitzenberger, Matthias Koch, Sam Lismont, Katarzyna Marta Zoltowska, Thomas Enzlein, Carsten Hopf, Martin Zacharias, Lucia Chavez-Gutierrez
Summary: This study investigates the interactions between an imidazole-based GSM and its target gamma-secretase-APP, and reveals that a part of the modulator interacts with a binding site on gamma-secretase, triggering rearrangements and stabilizing enzyme-substrate interactions.
Article
Chemistry, Medicinal
Annabelle Fueloep, Christian Marsching, Frederik Barka, Yasemin Ucal, Pauline Pfaender, Christiane A. Opitz, Guenes Barka, Carsten Hopf
Summary: On-tissue enzymatic digestion is crucial for analyzing tissue proteins and their N-glycan conjugates. However, the current sample preparation method is mainly carried out by specialized laboratories using home-built arrangements, which lack standardization. To address this, a digestion device that controls humidity and monitors the digestion process was designed.
Article
Chemistry, Multidisciplinary
Janne J. Wiedmann, Yelda N. Demirdoegen, Stefan Schmidt, Mariia A. Kuzina, Yanchen Wu, Fei Wang, Britta Nestler, Carsten Hopf, Pavel A. Levkin
Summary: In the current drug discovery process, the synthesis of compound libraries is separated from biological screenings due to the challenge of high-throughput purification. This study demonstrates a miniaturized high-throughput liquid-liquid extraction method on a chip, with efficiency comparable to large-scale extraction. The new purification method adds an important tool to accelerate drug discovery by combining chemical combinatorial synthesis with biological screenings on a miniaturized microarray platform.
Article
Biochemistry & Molecular Biology
Hagen M. Gegner, Thomas Naake, Aurelien Dugourd, Torsten Mueller, Felix Czernilofsky, Georg Kliewer, Evelyn Jaeger, Barbara Helm, Nina Kunze-Rohrbach, Ursula Klingmueller, Carsten Hopf, Carsten Mueller-Tidow, Sascha Dietrich, Julio Saez-Rodriguez, Wolfgang Huber, Rudiger Hell, Gernot Poschet, Jeroen Krijgsveld
Summary: Metabolomic and proteomic analyses of human plasma and serum samples have the potential to advance our understanding of disease biology. However, pre-analytical factors such as temperature and time can impact the integrity of the samples and there is a need for standardized operating procedures to ensure reliable data.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Qiuqin Zhou, Stefano Rizzo, Janina Oetjen, Annabelle Fueloep, Miriam Rittner, Hartmut Gillandt, Carsten Hopf
Summary: Insufficient vacuum stability of matrix chemicals is a major limitation in MALDI mass spectrometry imaging of large tissue sample cohorts. A photo-cleavable caged molecule, DMNB-2,5-DHAP, was designed and synthesized for lipid MALDI-MSI of mouse brain tissue sections. DMNB-2,5-DHAP exhibited vacuum stability in a high vacuum MALDI ion source and its uncaging process resulted in the generation of 2,5-DHAP with the assistance of the built-in laser in the MALDI ion source.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Multidisciplinary Sciences
Denis Abu Sammour, James L. Cairns, Tobias Boskamp, Christian Marsching, Tobias Kessler, Carina Ramallo Guevara, Verena Panitz, Ahmed Sadik, Jonas Cordes, Stefan Schmidt, Shad A. Mohammed, Miriam F. Rittel, Mirco Friedrich, Michael Platten, Ivo Wolf, Andreas von Deimling, Christiane A. Opitz, Wolfgang Wick, Carsten Hopf
Summary: Mass spectrometry imaging utilizes traditional ion images for metabolite visualization and analysis, but lacks consideration for nonlinearities and statistical significance. The computational framework moleculaR aims to improve signal reliability by Gaussian-weighting ion intensities and introduces probabilistic molecular mapping for statistically significant spatial abundance analysis. It allows cross-tissue comparisons and spatial statistical significance evaluation, facilitating the investigation of ion milieus, lipid remodeling pathways, and complex scores within the same image.
NATURE COMMUNICATIONS
(2023)
Article
Oncology
Miriam F. Rittel, Stefan Schmidt, Cleo-Aron Weis, Emrullah Birgin, Bjoern van Marwick, Matthias Raedle, Steffen J. Diehl, Nuh N. Rahbari, Alexander Marx, Carsten Hopf
Summary: The current focus of cancer pathology diagnosis is on histopathological analysis using stained tissue and immunohistochemistry of marker proteins. However, spatial omics imaging is an emerging diagnostic technology for identifying and classifying different cancer types. To address the need for preserving tissue-specific metabolomic states, we developed a device and corresponding workflows for multimodal spatial omics analysis of fresh-frozen needle biopsies, allowing for a spatial comparison between spectral profiles and tissue histology without the need for an extra biopsy.
Article
Biology
Thomas Kupke, Rabea M. Goetz, Florian M. Richter, Rainer Beck, Fabio Lolicato, Walter Nickel, Carsten Hopf, Britta Bruegger
Summary: The article introduces a simple assay, iCLiPSpy, for studying intramembrane-cleaving proteases (I-CLiPs) in vivo. This method allows for easy detection of enzyme activity and investigation of residues important for substrate binding and activity. It has the potential to be used as a screening assay for I-CLiP inhibitors or activators.
COMMUNICATIONS BIOLOGY
(2023)
Article
Medicine, Research & Experimental
Verena Panitz, Saga Koncarevic, Ahmed Sadik, Dennis Friedel, Tobias Bausbacher, Saskia Trump, Vadim Farztdinov, Sandra Schulz, Philipp Sievers, Stefan Schmidt, Ina Juergenson, Stephan Jung, Karsten Kuhn, Irada Pflueger, Suraj Sharma, Antje Wick, Pauline Pfaender, Stefan Selzer, Philipp Vollmuth, Felix Sahm, Andreas von Deimling, Ines Heiland, Carsten Hopf, Peter Schulz-Knappe, Ian Pike, Michael Platten, Wolfgang Wick, Christiane A. Opitz
Summary: This study utilized LC-MS/MS combined with chemical isobaric labeling to analyze serum samples from 43 recurrent glioblastoma patients and 43 healthy controls, revealing decreased levels of Trp and its metabolites in glioblastoma patients compared to controls. Higher tumor volume was associated with lower systemic metabolite levels, and lower systemic kynurenine levels correlated with worse overall survival. Additionally, analysis of scRNA-seq data showed that genes involved in Trp metabolism were expressed in various cell types in glioblastoma, with AHR activation observed in macrophages and T cells, and high AHR activity was linked to reduced overall survival in the glioblastoma TCGA dataset.