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.
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
Environmental Sciences
Yiping Yang, Jie Zhang, Xiaobo Yang, Zhiying Li, Jian Wang, Cailing Lu, Aruo Nan, Yunfeng Zou
Summary: The study revealed that excessive exposure to manganese inhibits the expression and activity of APP and α-secretase, leading to cognitive impairment, while showing no significant effect on β-secretase.
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
(2021)
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)
Review
Biochemistry & Molecular Biology
Vladimir Rudajev, Jiri Novotny
Summary: This article discusses the relationship between cholesterol and the development of Alzheimer's disease, as well as the influence of cholesterol on the production of amyloid beta (Aβ).
CELL AND BIOSCIENCE
(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)
Article
Biochemistry & Molecular Biology
Laura Garcia-Gonzalez, Jean-Michel Paumier, Laurence Louis, Dominika Pilat, Anne Bernard, Delphine Stephan, Nicolas Jullien, Frederic Checler, Emmanuel Nivet, Michel Khrestchatisky, Kevin Baranger, Santiago Rivera
Summary: The study revealed that MT5-MMP has control over the processing of APP and the release of Aβ through both proteolytic and non-proteolytic mechanisms, suggesting new insights for therapeutic regulation of AD-related pathology.
Article
Food Science & Technology
Zhipeng Kan, Yijun Wang, Qian Chen, Xiaoyu Tang, Henry J. Thompson, Jinbao Huang, Jinsong Zhang, Feng Gao, Yong Shen, Xiaochun Wan
Summary: In this study, it was found that green tea extract treatment significantly improved spatial learning and memory ability in 5XFAD mice, reduced the formation of A beta, and decreased the levels of related proteins. GTE also suppressed glial cell activation and inflammatory responses, while increasing synaptic protein levels.
MOLECULAR NUTRITION & FOOD RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Svetlana Sharifulina, Andrey Khaitin, Valeria Guzenko, Yuliya Kalyuzhnaya, Valentina Dzreyan, Alexandr Logvinov, Natalia Dobaeva, Yan Li, Lei Chen, Bin He, Svetlana Demyanenko
Summary: Our studies uncover changes in the expression of key components involved in amyloid precursor protein (APP) processing in neurons and astrocytes after photothrombotic stroke (PTS). We demonstrate an increase in N- and C-terminal fragments of APP in the cytoplasm of ischemic penumbra cells 24 hours after PTS, along with their co-immunoprecipitation with caveolin-1. The level of ADAM10 alpha-secretase decreases in the rat brain cortex on the first day after PTS. In astrocytes, but not in neurons, levels of gamma-secretase complex proteins presenilin-1 and nicastrin are elevated in the penumbra after PTS. These changes result in neuronal death and astrocyte activation during the early recovery period after PTS. Inhibiting caveolin-1 shifts APP processing towards Aβ synthesis, leading to astroglial activation. Inhibiting gamma-secretase down-regulates glial fibrillary acidic protein (GFAP) in astrocytes, prevents apoptosis in mouse cerebral cortex cells induced by PTS, and reduces the size of the infarcted area. Hence, novel gamma-secretase inhibitors hold promise as potential therapeutics for stroke treatment.
Article
Multidisciplinary Sciences
Naoto Watamura, Kaori Sato, Gen Shiihashi, Ayami Iwasaki, Naoko Kamano, Mika Takahashi, Misaki Sekiguchi, Naomi Mihira, Ryo Fujioka, Kenichi Nagata, Shoko Hashimoto, Takashi Saito, Toshio Ohshima, Takaomi C. Saido, Hiroki Sasaguri
Summary: Devoid of the Swedish mutations, the newly generated App knock-in mice (App(G-F) mice) show characteristics suitable for preclinical studies of beta-secretase inhibition in Alzheimer's disease (AD). Comparison of isogenic App knock-in lines reveals the influence of factors like C-terminal fragment beta (CTF-beta) and humanization of A beta on endosomal alterations.
Article
Biochemistry & Molecular Biology
Jowita Nowakowska-Golacka, Justyna Czapiewska, Hanna Sominka, Natalia Sowa-Rogozinska, Monika Slominska-Wojewodzka
Summary: EDEM1 is an important regulatory factor involved in APP metabolism, as it recognizes misfolded APP proteins and directs them to cytosol for degradation, leading to decreased secretion of Aβ.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Sandra Roselli, Tugce Munise Satir, Rafael Camacho, Stefanie Fruhwurth, Petra Bergstrom, Henrik Zetterberg, Lotta Agholme
Summary: Alzheimer's disease (AD) is characterized by the presence of amyloid beta (Aβ)-containing plaques. The production of Aβ from amyloid precursor protein (APP) by secretases has been extensively studied, but the exact mechanism of how the interaction between APP and secretases affects APP processing is not fully understood.
CELLULAR AND MOLECULAR NEUROBIOLOGY
(2023)
Article
Neurosciences
Jonathan Aow, Tzu-Rung Huang, Gopal Thinakaran, Edward H. Koo
Summary: In this study, the researchers found that there was a significant early and aberrant Bace1-mediated APP cleavage in the presence of APP/Bace1 co-expression. This led to disturbances in the trafficking of full-length APP (fl-APP) from the secretory pathway, resulting in a substantial loss of surface fl-APP and a marked reduction in APP internalization. Therefore, caution is needed when interpreting results where APP is detected only with a C-terminal tag in the presence of Bace1 co-expression, and previous findings may need to be reinterpreted if it is unclear whether fl-APP is present in normal physiological levels.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Cell Biology
Bo Zhou, Jacqueline G. Lu, Alberto Siddu, Marius Wernig, Thomas C. Sudhof
Summary: The APP-Swedish mutation in familial Alzheimer's disease enhances the production of Aβ peptides, leading to an increase in synaptic connectivity. This finding is consistent with the relative inefficacy of BACE1 and anti-Aβ treatments in Alzheimer's disease and suggests that elevated Aβ concentrations have long-term effects on disease pathogenesis.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Luana Naia, Makoto Shimozawa, Erika Bereczki, Xidan Li, Jianping Liu, Richeng Jiang, Romain Giraud, Nuno Santos Leal, Catarina Moreira Pinho, Erik Berger, Victoria Lim Falk, Giacomo Dentoni, Maria Ankarcrona, Per Nilsson
Summary: This study investigates the sequential onset of AD-like pathologies in App knock-in mice and reveals that energy metabolism is significantly altered at an early stage of pathology. As the pathology progresses, the brain shifts to a state of hypometabolism and synaptic abnormalities occur, including accumulation of synaptic vesicles and autophagosomes.
MOLECULAR PSYCHIATRY
(2023)
Review
Biochemistry & Molecular Biology
Douglas W. Ethell, Qingyan Fei
ANTIOXIDANTS & REDOX SIGNALING
(2009)
Article
Clinical Neurology
Carlo Paribello, Leeping Tao, Anthony Folino, Elizabeth Berry-Kravis, Michael Tranfaglia, Iryna M. Ethell, Douglas W. Ethell
Article
Neurosciences
Lillian A. Buhler, Ramsey Samara, Esther Guzman, Carole L. Wilson, Liljana Krizanac-Bengez, Damir Janigro, Douglas W. Ethell
Article
Biochemistry & Molecular Biology
Kai-Ti Lin, Slawomir Sloniowski, Douglas W. Ethell, Iryna M. Ethell
JOURNAL OF BIOLOGICAL CHEMISTRY
(2008)
Article
Neurosciences
Harpreet Sidhu, Lorraine E. Dansie, Peter W. Hickmott, Douglas W. Ethell, Iryna M. Ethell
JOURNAL OF NEUROSCIENCE
(2014)
Article
Neurosciences
Chuanhai Cao, Gary W. Arendash, Alexander Dickson, Malgorzata B. Mamcarz, Xiaoyang Lin, Douglas W. Ethell
NEUROBIOLOGY OF DISEASE
(2009)
Article
Neurosciences
L. E. Dansie, K. Phommahaxay, A. G. Okusanya, J. Uwadia, M. Huang, S. E. Rotschafer, K. A. Razak, D. W. Ethell, I. M. Ethell
Article
Multidisciplinary Sciences
D. Joshua Cameron, Cooper Galvin, Tursun Alkam, Harpreet Sidhu, John Ellison, Salvadore Luna, Douglas W. Ethell
Article
Multidisciplinary Sciences
Salvadore Luna, D. Joshua Cameron, Douglas W. Ethell
Article
Psychiatry
A. N. Begum, C. Cunha, H. Sidhu, T. Alkam, J. Scolnick, E. R. Rosario, D. W. Ethell
TRANSLATIONAL PSYCHIATRY
(2014)
Article
Multidisciplinary Sciences
Douglas W. Ethell, D. Joshua Cameron
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
(2014)
Article
Cell Biology
Noora Putkonen, Asta Laiho, Doug Ethell, Juha Pursiheimo, Anna-Kaisa Anttonen, Juho Pitkonen, Adriana M. Gentile, Yolanda de Diego-Otero, Maija L. Castren
Article
Ophthalmology
Khomthorn Cunvong, Daniel Huffmire, Douglas W. Ethell, D. Joshua Cameron
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2013)
Article
Genetics & Heredity
T. V. Bilousova, L. Dansie, M. Ngo, J. Aye, J. R. Charles, D. W. Ethell, I. M. Ethell
JOURNAL OF MEDICAL GENETICS
(2009)