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.
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
Neurosciences
Hirotaka Watanabe, Kent Imaizumi, Tetsuo Cai, Zhi Zhou, Taisuke Tomita, Hideyuki Okano
Summary: Genetic mutations in presenilin genes (PS1, PS2) are associated with familial Alzheimer's disease (AD). This study investigated the physiological roles of PS in human neurons using iPSCs and generated PS-null human cortical neurons. PS was found to play essential roles in Notch signaling and Aβ production, with PS1 and PS2 showing different effects on cleavage of different substrates.
Article
Geriatrics & Gerontology
Kelly Virecoulon Giudici, Philipe de Souto Barreto, Sophie Guyonnet, John E. Morley, Andrew D. Nguyen, Geetika Aggarwal, Angelo Parini, Yan Li, Randall John Bateman, Bruno Vellas Vellas, MAPT DSA Grp
Summary: There is evidence of an association between inflammation pathways and plasma markers of neurodegeneration, highlighting the importance of monitoring this risk in older adults.
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
(2023)
Article
Biology
Lukas P. Feilen, Shu-Yu Chen, Akio Fukumori, Regina Feederle, Martin Zacharias, Harald Steiner
Summary: The activity of intramembrane proteases is modulated by lipid bilayers, and this study reveals the mechanism linking lipid environment to structural dynamics. The lipid bilayer plays a critical role in stabilizing the structure and arranging the active site of intramembrane protease.
Article
Cell Biology
Tobias A. Weber, Johan Lundkvist, Johanna Wanngren, Hlin Kvartsberg, ShaoBo Jin, Pia Larssen, Dan Wu, Daniel Oliveira, Karolina Minta, Gunnar Brinkmalm, Henrik Zetterberg, Kaj Blennow, Gunnar Nordvall, Bengt Winblad, Erik Portelius, Helena Karlstrom
Summary: The study demonstrates that gamma-secretase modulators selectively affect the production of Aβ, with a particular modulation on the Aβ-like proteins derived from EphA4.
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
(2022)
Review
Geriatrics & Gerontology
Jiaxuan Li, Xin Wu, Xin Tan, Shixin Wang, Ruisi Qu, Xiaofeng Wu, Zhouqing Chen, Zhong Wang, Gang Chen
Summary: This meta-analysis found that anti-A beta drugs do not have an effect on cognitive performance in AD patients, but monoclonal antibodies can delay cognitive decline. Development of other types of anti-A beta drugs should proceed with caution.
FRONTIERS IN AGING NEUROSCIENCE
(2023)
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)
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
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
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
Cell Biology
Olav M. Andersen, Nikolaj Bogh, Anne M. Landau, Gro G. Ploen, Anne Mette G. Jensen, Giulia Monti, Benedicte P. Ulhoi, Jens R. Nyengaard, Kirsten R. Jacobsen, Margarita M. Jorgensen, Ida E. Holm, Marianne L. Kristensen, Aage Kristian O. Alstrup, Esben S. S. Hansen, Charlotte E. Teunissen, Laura Breidenbach, Mathias Droescher, Ying Liu, Hanne S. Pedersen, Henrik Callesen, Yonglun Luo, Lars Bolund, David J. Brooks, Christoffer Laustsen, Scott A. Small, Lars F. Mikkelsen, Charlotte B. Sorensen
Summary: This study developed a model of SORL1 haploinsufficiency using gene editing in minipigs, showing that this model can mimic the preclinical features of AD and providing functional support for the theory that SORL1 haploinsufficiency leads to AD.
CELL REPORTS MEDICINE
(2022)
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
Biochemistry & Molecular Biology
Soumyabrata Banerjee, Biswajit Mukherjee, Mrinal K. Poddar, Gary L. Dunbar
Summary: The study found that carnosine treatments improved cognitive function deficits induced by aging, reduced beta-sheets in the secondary structure of A beta protein, and mitigated the decrease in carnosine levels and spine density in the examined brain regions. These results suggest that carnosine can attenuate aging-induced conformational changes in A beta secondary structure and cognitive impairment.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Neurosciences
Zunyu Ke, Yu Zhao, Chuanling Wang, Zhiyou Cai
INTERNATIONAL JOURNAL OF NEUROSCIENCE
(2018)
Review
Clinical Neurology
Zhiyou Cai, Cheng-Qun Wan, Zhou Liu
JOURNAL OF NEUROLOGY
(2017)
Article
Pharmacology & Pharmacy
Wenbo He, Chuanling Wang, Yi Chen, Yongli He, Zhiyou Cai
PHARMACOLOGICAL REPORTS
(2017)
Review
Neurosciences
Yongli He, Zhiyou Cai, Yangmei Chen
INTERNATIONAL JOURNAL OF NEUROSCIENCE
(2018)
Review
Neurosciences
Sinian Li, Yiming Shao, Kanglan Li, Changmei HuangFu, Wenjie Wang, Zhou Liu, Zhiyou Cai, Bin Zhao
JOURNAL OF ALZHEIMERS DISEASE
(2018)
Review
Neurosciences
Zhiyou Cai, Pei-Feng Qiao, Cheng-Qun Wan, Min Cai, Nan-Kai Zhou, Qin Li
JOURNAL OF ALZHEIMERS DISEASE
(2018)
Review
Cell Biology
Zhi-You Cai, Ming Xiao, Sohel H. Quazi, Zun-Yu Ke
NEURAL REGENERATION RESEARCH
(2018)
Review
Medicine, Research & Experimental
Z. Cai, Y. He, Y. Chen
CURRENT MOLECULAR MEDICINE
(2018)
Article
Medicine, Research & Experimental
Z. Cai, C. Wang, Y. Chen, W. He
CURRENT MOLECULAR MEDICINE
(2018)
Article
Neurosciences
Zhiyou Cai, Wenbo He, Feng-Juan Zhuang, Yan Chen
INTERNATIONAL JOURNAL OF NEUROSCIENCE
(2019)
Review
Neurosciences
Lianying Jiang, Jiafeng Wang, Zhigang Wang, Wenhui Huang, Yixia Yang, Zhiyou Cai, Keshen Li
JOURNAL OF ALZHEIMERS DISEASE
(2018)
Article
Medicine, Research & Experimental
Yu Zhao, Zunyu Ke, Wenbo He, Zhiyou Cai
JOURNAL OF INTERNATIONAL MEDICAL RESEARCH
(2019)
Article
Geriatrics & Gerontology
Zhenting Huang, Chengqun Wan, Yangyang Wang, Peifeng Qiao, Qian Zou, Jingxi Ma, Zhou Liu, Zhiyou Cai
Summary: The study demonstrates that GMOL can ameliorate cognitive impairment in normal aged SD rats by enhancing the expression of memory-related proteins, inhibiting inflammatory factors, and improving spatial learning and memory ability.
EXPERIMENTAL AGING RESEARCH
(2021)
Article
Cell Biology
Jie Wen, Yangyang Wang, Chuanling Wang, Minghao Yuan, Fei Chen, Qian Zou, Zhiyou Cai, Bin Zhao
Summary: Dietary habits contribute to the characteristics of Alzheimer's disease (AD) and cognitive impairment, partly due to the accumulation of hyperphosphorylated Tau protein. A high-fat diet damages the brain and impairs synaptic function, leading to cognitive decline. The mechanism involves decreased expression of synaptophysin and brain-derived neurotrophic factor, impaired mitophagy, and increased Tau protein phosphorylation.
OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
(2023)