Article
Chemistry, Medicinal
Richard A. Hartz, Vijay T. Ahuja, Guanglin Luo, Ling Chen, Prasanna Sivaprakasam, Hong Xiao, Carol M. Krause, Wendy J. Clarke, Songmei Xu, John S. Tokarski, Kevin Kish, Hal Lewis, Nicolas Szapiel, Ramu Ravirala, Sayali Mutalik, Deepa Nakmode, Devang Shah, Catherine R. Burton, John E. Macor, Gene M. Dubowchik
Summary: Glycogen synthase kinase-3 (GSK-3) is a crucial regulator of cellular functions, implicated in diseases such as Alzheimer's disease, mood disorders, diabetes, and cancer. Its role in the production of abnormal tau protein in neurofibrillary tangles associated with Alzheimer's disease has been established. The synthesis and evaluation of pyrimidine-based GSK-3 inhibitors led to the identification of highly potent compounds that effectively lowered phosphorylated tau levels in a mouse model of Alzheimer's disease.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Cell Biology
Carmen Laura Sayas, Jesus Avila
Summary: GSK-3 is a crucial player in AD pathology, contributing to the hyperphosphorylation of tau protein and involvement in various neuronal processes that are dysregulated during AD pathogenesis. Targeting GSK-3 or GSK-3-phosphorylated tau could hold potential for developing AD therapies.
Article
Biochemistry & Molecular Biology
Jie Ai, Hongyan Wang, Peng Chu, Abdullah Shopit, Mengyue Niu, Nisar Ahmad, Tsehaye Tesfaldet, Fu Han Wang, Jia Ni Fang, Xiaodong Li, Shi Jie Tang, Qing Ju Han, Guozhu Han, Jinyong Peng, Zeyao Tang
Summary: The study demonstrates that phosphocreatine (PCr) can protect neuronal cells from A beta protein-induced injury through various pathways, such as reducing oxidative stress and apoptotic pathway activities, as well as modulating Tau protein phosphorylation and other key signaling pathways.
FREE RADICAL BIOLOGY AND MEDICINE
(2021)
Article
Environmental Sciences
Yali Zhang, Xing Fan, Zhangyao Su, Tianli Yuan, Haimeng Yin, Haohao Gu, Yue Zuo, Shiyin Chen, Hongyu Zhou, Gaoxing Su
Summary: Metformin effectively prevents tau hyperphosphorylation caused by MC-LR, improving the AD-like phenotype. This preventive effect is mainly mediated by mTOR-dependent PP2A and GSK-3 beta activation.
ENVIRONMENTAL TOXICOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Yanwen Wang, Miao Cai, Yue Lou, Siran Zhang, Xiaoli Liu
Summary: The study demonstrated that the upregulation of LncRNA ZBTB20-AS1 suppressed the expression of ZBTB20 and promoted the expression of GSK-3 beta and phosphorylation of Tau, thus contributing to the development of Alzheimer's disease.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Ana Claudia Amaral, Beatriz G. Perez-Nievas, Michael Siao Tick Chong, Alicia Gonzalez-Martinez, Herminia Argente-Escrig, Sara Rubio-Guerra, Caitlin Commins, Serra Muftu, Bahareh Eftekharzadeh, Eloise Hudry, Zhanyun Fan, Prianca Ramanan, Shuko Takeda, Matthew P. Frosch, Susanne Wegmann, Teresa Gomez-Isla
Summary: Partial reduction of GSK-3 beta can decrease pathological tau changes in the brain of AD mice, including hyperphosphorylation and aggregation, reducing tau protein spread between neurons. This suggests GSK-3 beta as a promising therapeutic target for AD and other tauopathies.
Article
Behavioral Sciences
Xiaoqin Tan, Zhibin Liang, Yingui Li, Yingkun Zhi, Lang Yi, Shasha Bai, Kelly H. Forest, Robert A. Nichols, Yan Dong, Qing X. Li
Summary: Isoorientin, a selective inhibitor of GSK-3 beta, shows therapeutic potential in attenuating AD pathogenic hallmarks and improving cognitive function in transgenic mouse models.
BEHAVIOURAL BRAIN RESEARCH
(2021)
Article
Neurosciences
Shaohui Wang, Yao Jiang, Yabo Liu, Qianhui Liu, Hongwei Sun, Mengjie Mei, Xiaomei Liao
Summary: This study demonstrates that ferroptosis promotes abnormal aggregation of tau protein and may serve as a promising therapeutic target for tauopathies.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Biochemical Research Methods
Shin-ichi Hisanaga, Ambika Krishnankutty, Taeko Kimura
Summary: Phosphorylation is an important posttranslational modification that regulates various cellular processes. Phos-tag is a useful technique for analyzing the in vivo phosphorylation of proteins. It overcomes the challenges associated with quantifying site-specific phosphorylation and provides valuable insights into the phosphorylation of different proteins.
JOURNAL OF PROTEOMICS
(2022)
Article
Neurosciences
Danny Baltissen, Charlotte S. Bold, Lena Rehra, Marija Banicevic, Justus Fricke, Jennifer Just, Susann Ludewig, Christian J. Buchholz, Martin Korte, Ulrike C. Mueller
Summary: The Tau protein is phosphorylated by multiple kinases and the accumulation of hyperphosphorylated Tau species is a major characteristic of Alzheimer's disease (AD). AD is also characterized by the presence of A beta plaques derived from the beta-amyloid precursor protein APP. APP processing along the non-amyloidogenic pathway results in the secretion of neurotrophic APPs alpha, which has therapeutic effects in transgenic AD model mice. In this study, the researchers investigated the potential of APPs alpha to regulate the Tau kinases GSK3 beta and CDK5 in a mouse model of tauopathy, and found that APPs alpha restored normal kinase activity and mitigated Tau-induced pathology.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Review
Chemistry, Medicinal
Neha Chauhan, Swati Paliwal, Smita Jain, Kanika Verma, Sarvesh Paliwal, Swapnil Sharma
Summary: Alzheimer's disease is a major health and socioeconomic burden worldwide, characterized by neuronal loss, memory loss, and cognitive impairment. GSK-3 beta plays a significant role in the molecular mechanisms of AD progression, making it a potential therapeutic target for the disease.
MINI-REVIEWS IN MEDICINAL CHEMISTRY
(2022)
Review
Oncology
Alberto M. Martelli, Camilla Evangelisti, Francesca Paganelli, Francesca Chiarini, James A. McCubrey
Summary: GSK-3 consists of two isoforms, alpha and beta, that are constitutively active but can be inactivated through phosphorylation by upstream kinases. It was initially considered a tumor suppressor, but it has also been found to have oncogenic properties in promoting pathways critical for cancer cell proliferation, survival, and drug-resistance.
Article
Chemistry, Medicinal
Zhongwen Luo, Shang Li, Yonglei Zhang, Fucheng Yin, Heng Luo, Xinye Chen, Ningjie Cui, Siyuan Wan, Xinxin Li, Lingyi Kong, Xiaobing Wang
Summary: Neuronal cells overexpressing phosphorylated Tau proteins increase susceptibility to oxidative stress. Regulation of GSK-3 beta and reduction of Tau protein hyperphosphorylation, as well as alleviation of oxidative stress, may be effective in preventing or treating Alzheimer's disease (AD). The compound KWLZ-9e showed potential GSK-3 beta inhibition and neuroprotective capacity, and it could alleviate oxidative stress and improve learning and memory impairments in an AD model, making it a promising lead for AD treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Richard A. Hartz, Vijay T. Ahuja, Prasanna Sivaprakasam, Hong Xiao, Carol M. Krause, Wendy J. Clarke, Kevin Kish, Hal Lewis, Nicolas Szapiel, Ramu Ravirala, Sayali Mutalik, Deepa Nakmode, Devang Shah, Catherine R. Burton, John E. Macor, Gene M. Dubowchik
Summary: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates various cellular processes and has been implicated in diseases such as Alzheimer's disease, type 2 diabetes, cancer, and mood disorders. This study describes the design and synthesis of imidazo[1,2-b]pyridazine derivatives as GSK-3 beta inhibitors. Structure-activity relationship studies led to the discovery of potent GSK-3 beta inhibitors. In vivo studies in a triple-transgenic mouse Alzheimer's disease model showed that compound 47 is a brain-penetrant, orally bioavailable GSK-3 beta inhibitor that significantly lowers phosphorylated tau levels.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Mohammad Rafi Khezri, Keyvan Yousefi, Negin Mahboubi, Darya Hodaei, Morteza Ghasemnejad-Berenji
Summary: Alzheimer's disease (AD) is a common neurodegenerative disorder worldwide, and its association with diseases like diabetes has been well-studied. Metformin, a medication commonly used for type 2 diabetes, has shown potential disease-modifying effects on various aspects of AD pathophysiology.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Cell Biology
Ching-Tzu Wang, Yi-Chun Chen, Yi-Yun Wang, Ming-Hao Huang, Tzu-Li Yen, Hsun Li, Cyong-Jhih Liang, Tzu-Kang Sang, Shih-Ci Ciou, Chiou-Hwa Yuh, Chao-Yung Wang, Theodore J. Brummel, Horng-Dar Wang
Article
Biochemistry & Molecular Biology
Abirami Santhanam, Wen-Hsin Peng, Ya-Ting Yu, Tzu-Kang Sang, Guang-Chao Chen, Tzu-Ching Meng
MOLECULAR AND CELLULAR BIOLOGY
(2014)
Article
Biochemistry & Molecular Biology
Hsin-Tzu Chan, Tian-Ren Lee, Shun-Hong Huang, Hsiao-Yun Lee, Tzu-kang Sang, Hong-Lin Chan, Ping-Chiang Lyu
MOLECULAR BIOSYSTEMS
(2012)
Article
Genetics & Heredity
Ya-Chu Chang, Wan-Tzu Hung, Yun-Chin Chang, Henry C. Chang, Chia-Lin Wu, Ann-Shyn Chiang, George R. Jackson, Tzu-Kang Sang
Review
Biochemistry & Molecular Biology
Hao Chi, Hui-Yun Chang, Tzu-Kang Sang
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2018)
Article
Multidisciplinary Sciences
Ya-Chu Chang, Yu-Xiang Peng, Bo-Hua Yu, Henry C. Chang, Pei-Shin Liang, Ting-Yi Huang, Chao-Jie Shih, Li-An Chu, Tzu-Kang Sang
Summary: Disruption of VCP causes progressive nuclear size increase, connecting DNA damage to enlarged nuclei; Accumulation of MDC1 stabilizes p53A, potentially contributing to nuclear size increase; Cells regulate nuclear size by maintaining a constant cytoplasm to nucleus volume ratio, with the role of DNA damage in this process remaining poorly explored.
NATURE COMMUNICATIONS
(2021)
Review
Cell Biology
Hui-Yun Chang, Tzu-Kang Sang, Ann-Shyn Chiang
JOURNAL OF BIOMEDICAL SCIENCE
(2018)
Article
Cardiac & Cardiovascular Systems
Meera C. Viswanathan, Anna C. Blice-Baum, Tzu-Kang Sang, Anthony Cammarato
JOURNAL OF CARDIOVASCULAR DEVELOPMENT AND DISEASE
(2016)
Review
Neurosciences
Tzu-Kang Sang, Hui-Yun Chang, George M. Lawless, Anuradha Ratnaparkhi, Lisa Mee, Larry C. Ackerson, Nigel T. Maidment, David E. Krantz, George R. Jackson
JOURNAL OF NEUROSCIENCE
(2007)
Article
Neurosciences
Stanislav L. Karsten, Tzu-Kang Sang, Lauren T. Gehman, Shreyasi Chatterjee, Jiankai Liu, George M. Lawless, Soma Sengupta, Robert W. Berry, Justine Pomakian, Hyun S. Oh, Cordula Schulz, Koon-Sea Hui, Martina Wiedau-Pazos, Harry V. Vinters, Lester I. Binder, Daniel H. Geschwind, George R. Jackson
Article
Biochemistry & Molecular Biology
L Mee, H Honkala, O Kopra, J Vesa, S Finnilä, I Visapää, TK Sang, GR Jackson, R Salonen, M Kestilä, L Peltonen
HUMAN MOLECULAR GENETICS
(2005)
Article
Biochemistry & Molecular Biology
TK Sang, CJ Li, WC Liu, A Rodriguez, JM Abrams, SL Zipursky, GR Jackson
HUMAN MOLECULAR GENETICS
(2005)
Meeting Abstract
Geriatrics & Gerontology
GR Jackson, TK Sang
NEUROBIOLOGY OF AGING
(2004)
Article
Neurosciences
GR Jackson, M Wiedau-Pazos, TK Sang, N Wagle, CA Brown, S Massachi, DH Geschwind