Article
Clinical Neurology
Jean-Pierre Bellier, Yuqi Cai, Sarah M. Alam, Thorsten Wiederhold, Arica Aiello, Jonathan S. Vogelgsang, Sabina Berretta, Jasmeer P. Chhatwal, Dennis J. Selkoe, Lei Liu
Summary: A wide array of post-translational modifications of the tau protein occurs in Alzheimer's disease (AD) and they are critical to pathogenesis and biomarker development. Several promising tau markers, pT181, pT217, and pT231, rely on increased phosphorylation within a common molecular motif threonine-proline-proline (TPP). The regional variability of pTPP tau suggests that examining different phosphorylation sites is essential for a comprehensive assessment of tau pathology.
ALZHEIMERS & DEMENTIA
(2023)
Review
Biochemistry & Molecular Biology
Huiqin Zhang, Wei Wei, Ming Zhao, Lina Ma, Xuefan Jiang, Hui Pei, Yu Cao, Hao Li
Summary: Extracellular neuritic plaques and intracellular neurofibrillary tangles, composed of amyloid-beta and phosphorylated tau protein respectively, are hallmark proteins of Alzheimer's disease. The interactions between these proteins have been extensively studied, with A beta accelerating tau phosphorylation, tau mediating A beta toxicity, and potential synergistic effects on microglial cells and astrocytes. Understanding these interactions may lead to new interventions against Alzheimer's disease.
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
(2021)
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
Chemistry, Multidisciplinary
Ly Thi Huong Luu Le, Jeeyoung Lee, Dongjoon Im, Sunha Park, Kyoung-Doo Hwang, Jung Hoon Lee, Yanxialei Jiang, Yong-Seok Lee, Young Ho Suh, Hugh I. Kim, Min Jae Lee
Summary: In tauopathy conditions, tau protein aggregates into insoluble filaments, contributing to the pathology of Alzheimer's disease. This study demonstrates that a specific region of tau, called tau AD nucleation core (tau-AC), is responsible for initiating self-aggregation of tau and recruiting full-length tau to form filaments. Phosphorylation of tau-AC reduces its ability to oligomerize and seed tau aggregation. Importantly, the presence of tau-AC species impairs neuronal function and memory retrieval, highlighting its significance as a therapeutic target for Alzheimer's disease.
Article
Neurosciences
Philip Regan, Scott J. Mitchell, Seung-Chan Kim, Younbok Lee, Jee Hyun Yi, Saviana A. Barbati, Christopher Shaw, Kwangwook Cho
Summary: The study revealed that pTau decreases the binding between tau and PACSIN1 proteins at specific serine residues, leading to PACSIN1-dependent functional and structural synapse weakening. Knock-down of tau or PACSIN1 increases AMPAR-mediated current at extrasynaptic regions, indicating their role in affecting AMPAR trafficking.
JOURNAL OF NEUROSCIENCE
(2021)
Review
Immunology
Yijun Chen, Yang Yu
Summary: Alzheimer's Disease (AD) is mostly responsible for dementia, characterized by neuritic plaques and neurofibrillary tangles containing aggregated β-amyloid (Aβ) and hyperphosphorylated tau protein. Recent focus has been on disease-modifying therapy targeting Aβ, although the efficacy and long-term safety of such drugs are still controversial. Tau has gained attention as a therapeutic target due to its association with cognitive dysfunction. Inflammation, especially neuroinflammation, is linked to AD and tau pathology. Understanding the relationship between tau pathology and neuroinflammation will contribute to discovering therapeutic targets for AD and other tau-related diseases.
JOURNAL OF NEUROINFLAMMATION
(2023)
Article
Clinical Neurology
Binita Rajbanshi, Anuj Guruacharya, James W. Mandell, George S. Bloom
Summary: Tau phosphorylation at T217 increases as Alzheimer's disease progresses and is associated with diseased neurons. Extracellular tau oligomers can induce an increase in tau(pT217). Phosphorylation reduces tau's affinity for microtubules.
ALZHEIMERS & DEMENTIA
(2023)
Article
Cell Biology
M. Bell-Simons, S. Buchholz, J. Klimek, H. Zempel
Summary: This study used a laser-based axotomy model combined with confocal microscopy to investigate the distribution of Tau protein in axons and its relationship with protein transport. The results suggest that axonal damage does not lead to the accumulation of Tau protein in the cell body or an increase in AT8 Tau phosphorylation.
CELLULAR AND MOLECULAR NEUROBIOLOGY
(2023)
Article
Clinical Neurology
Eva Davila-Bouziguet, Arnau Casoliba-Melich, Georgina Targa-Fabra, Lorena Galera-Lopez, Andres Ozaita, Rafael Maldonado, Jesus Avila, Jose M. Delgado-Garcia, Agnes Gruart, Eduardo Soriano, Marta Pascual
Summary: Alzheimer's disease is a neurodegenerative disease characterized by the accumulation of amyloid-beta and hyperphosphorylated Tau, imbalanced neuronal activity, and cognitive deficits. A new clinical entity has been identified, which shows amyloid-beta and Tau pathologies but preserved cognition. A study using mice models found that J20/VLW mice, which accumulate amyloid-beta and hyperphosphorylated Tau, exhibit preserved hippocampal rhythmic activity and cognition, while single mutant mice show significant alterations. Furthermore, the overexpression of mutant human Tau in the hippocampal interneurons leads to a specific hyperphosphorylated Tau signature. These findings contribute to understanding the mechanisms underlying cognitive preservation in non-demented individuals with Alzheimer's disease neuropathology.
Article
Clinical Neurology
Yalun Zhang, Yi Zhang, Yahyah Aman, Cheung Toa Ng, Wing-Hin Chau, Zhigang Zhang, Ming Yue, Christopher Bohm, Yizhen Jia, Siwen Li, Qiuju Yuan, Jennifer Griffin, Kin Chiu, Dana S. M. Wong, Binbin Wang, Dongyan Jin, Ekaterina Rogaeva, Paul E. Fraser, Evandro F. Fang, Peter St George-Hyslop, You-Qiang Song
Summary: Research has shown that the transcription factor PAX6 is increased in Alzheimer's disease, playing a key role in the hyperphosphorylation of tau protein induced by amyloid-beta. Downregulation of PAX6 can protect against amyloid-beta-induced neuronal death. This study provides novel potential targets for pharmaceutical intervention by modulating signaling pathways involving CDK/pRB/E2F1.
Article
Neurosciences
Xin Wang, Qian Liu, Xiao-Guang Li, Qiu-Zhi Zhou, Dong-Qin Wu, Shi-Hong Li, Yan-Chao Liu, Jian-Zhi Wang
Summary: The study showed that T217-phosphorylation exacerbates wild-type tau hyperphosphorylation with aggravated tau cleavage/fibrillization and cognitive impairments; however, overexpressing T217E on the basis P301L does not exacerbate tau phosphorylation or the P301L-induced cognitive deficits, although it aggravates tau cleavage and propagation.
JOURNAL OF ALZHEIMERS DISEASE
(2021)
Article
Clinical Neurology
Yoon A. Kim, Tohid Siddiqui, Jennifer Blaze, Mehmet Ilyas Cosacak, Tristan Winters, Atul Kumar, Ellen Tein, Andrew A. Sproul, Andrew F. Teich, Francesca Bartolini, Schahram Akbarian, Caghan Kizil, Gunnar Hargus, Ismael Santa-Maria
Summary: Epitranscriptomic regulation plays a role in brain function and can be implicated in diseases like Alzheimer's disease. This study investigates NSun2, an RNA methyltransferase, in Alzheimer's disease and finds decreased NSun2 expression and increased pTau/NSun2 ratio in the brains of patients. Using animal models and neuronal cultures, the study shows that NSun2 deficiency exacerbates tau phosphorylation, while overexpression of NSun2 partially reverses tau toxicity. These findings suggest that NSun2 could be a potential therapeutic target for Alzheimer's disease.
ACTA NEUROPATHOLOGICA
(2023)
Article
Environmental Sciences
Shenya Xu, Zeyun Yang, Ye Zhi, Shali Yu, Tao Zhang, Junkang Jiang, Jun Tang, Hongsen He, Ming Lu, Xiaoke Wang, Qiyun Wu, Xinyuan Zhao
Summary: The study revealed that exposure to antimony can lead to neuronal apoptosis and increase the risk of Alzheimer's disease. Detection of A beta and NFTs accumulation in the brains of mice exposed to antimony showed A beta accumulation after 4 weeks, A beta accumulation and tau phosphorylation after 8 weeks, and complete AD hallmarks after 1 year.
SCIENCE OF THE TOTAL ENVIRONMENT
(2021)
Article
Plant Sciences
Caixia Zang, Hui Liu, Junmei Shang, Hanyu Yang, Lu Wang, Chanjuan Sheng, Zihong Zhang, Xiuqi Bao, Yang Yu, Xinsheng Yao, Dan Zhang
Summary: The study demonstrates that GJ-4 improves cognitive deficits in APP/PS1 transgenic mice by reducing A beta levels, inhibiting tau protein phosphorylation, and suppressing neuroinflammatory responses. These findings provide a basis for further development of GJ-4 as a potential treatment for AD.
Article
Neurosciences
Biao Luo, Jian Chen, Gui-Feng Zhou, Xiao-Yong Xie, Jing Tang, Qi-Xin Wen, Li Song, Shi-Qi Xie, Yan Long, Guo-Jun Chen, Xiao-Tong Hu
Summary: Apicidin improves AD symptoms in APP/PS1 mice by regulating the expression of ADAM10, leading to a decrease in A beta levels rather than phosphorylation of tau.
CNS NEUROSCIENCE & THERAPEUTICS
(2023)
Editorial Material
Pharmacology & Pharmacy
Wendy Noble, Maria Jimenez-Sanchez, Beatriz G. Perez-Nievas, Diane P. Hanger
EXPERT OPINION ON DRUG DISCOVERY
(2020)
Editorial Material
Neurosciences
Yumiko Motoi, Diane P. Hanger, Masato Hasegawa
FRONTIERS IN NEUROSCIENCE
(2020)
Article
Biochemistry & Molecular Biology
Alice Prigent, Guillaume Chapelet, Adrien De Guilliem de Lataillade, Thibauld Outlier, Emilie Durieu, Arnaud Bourreille, Emilie Duchalais, Kevin Hardonniere, Michel Neunlist, Wendy Noble, Saadia Kercline-Romer, Pascal Derkinderen, Malvyne Rolli-Derkinderen
Article
Neurosciences
Dawn H. W. Lau, Sebastien Paillusson, Naomi Hartopp, Huzefa Rupawala, Gabor M. Morotz, Patricia Gomez-Suaga, Jenny Greig, Claire Troakes, Wendy Noble, Christopher C. J. Miller
NEUROBIOLOGY OF DISEASE
(2020)
Review
Clinical Neurology
Matthew J. Reid, Paula Beltran-Lobo, Louisa Johnson, Beatriz Gomez Perez-Nievas, Wendy Noble
FRONTIERS IN NEUROLOGY
(2020)
Review
Biochemistry & Molecular Biology
Pascal Derkinderen, Malvyne Rolli-Derkinderen, Guillaume Chapelet, Michel Neunlist, Wendy Noble
Summary: The enteric nervous system, often referred to as the 'second brain', shares many features with the central nervous system and may be susceptible to neurodegenerative diseases similar to those affecting the brain. Current studies focus on the expression and phosphorylation pattern of tau protein in the enteric nervous system, exploring the potential occurrence of 'enteric tauopathies'.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Erica Staurenghi, Valentina Cerrato, Paola Gamba, Gabriella Testa, Serena Giannelli, Valerio Leoni, Claudio Caccia, Annalisa Buffo, Wendy Noble, Beatriz Gomez Perez-Nievas, Gabriella Leonarduzzi
Summary: Among the brain hallmarks of Alzheimer's disease, reactive astrocytes are correlated with neuronal loss and cognitive deficits, while alterations in brain cholesterol metabolism contribute to AD pathogenesis. Oxysterols in AD brains induce astrocyte reactivity and the release of mediators that impact neuronal health and synapses, with lipocalin-2 playing a key role in mediating the synaptotoxic effect of oxysterol-treated astrocytes.
Article
Cell Biology
Patricia Gomez-Suaga, Gabor M. Morotz, Andrea Markovinovic, Sandra M. Martin-Guerrero, Elisavet Preza, Natalia Arias, Keith Mayl, Afra Aabdien, Vesela Gesheva, Agnes Nishimura, Ambra Annibali, Younbok Lee, Jacqueline C. Mitchell, Selina Wray, Christopher Shaw, Wendy Noble, Christopher C. J. Miller
Summary: This study reveals that hexanucieotide repeat expansions in C9orf72 disrupt the ER-mitochondria signalling and VAPB-PTPIP51 tethers, leading to neurotoxicity. The interaction between VAPB-PTPIP51 is disrupted by neurotoxic DPRs, potentially involving the activation of GSK3β. Furthermore, these DPRs also disrupt the delivery of Ca2+ from ER stores to mitochondria, which is a primary function of the VAPB-PTPIP51 tethers. These findings identify a new molecular target for mutant C9orf72-mediated toxicity.
Article
Immunology
Beatriz G. Perez-Nievas, Louisa Johnson, Paula Beltran-Lobo, Martina M. Hughes, Luciana Gammallieri, Francesca Tarsitano, Monika A. Myszczynska, Irina Vazquez-Villasenor, Maria Jimenez-Sanchez, Claire Troakes, Stephen B. Wharton, Laura Ferraiuolo, Wendy Noble
Summary: The pathological interactions between beta-amyloid (A beta) and tau contribute to synapse loss and cognitive decline in Alzheimer's disease (AD). Reactive astrocytes play a prominent role in AD brain and exacerbate the synaptotoxic effects of A beta through the interaction of astrocytic CXCL1 and neuronal CXCR2 receptors, suggesting a potential novel therapeutic target.
JOURNAL OF NEUROINFLAMMATION
(2021)
Article
Biochemistry & Molecular Biology
Chen Lyu, Stefano Da Vela, Youssra Al-Hilaly, Karen E. Marshall, Richard Thorogate, Dmitri Svergun, Louise C. Serpell, Annalisa Pastore, Diane P. Hanger
Summary: Tau35 is a truncated form of tau found in human brain in certain tauopathies, and its expression in mice recapitulates key features of human disease including increased tau phosphorylation and cognitive/motor dysfunction. Structural characterization revealed that Tau35 exhibits higher rigidity and a higher propensity to aggregate compared to longer tau isoforms 2N3R and 2N4R. Tau35 aggregates are morphologically similar to previously reported tau fibrils but more densely packed, shedding light on their potentially damaging role in tauopathies.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Clinical Neurology
Cindy C. C. Pang, Maja H. Sorensen, Krit Lee, Kelvin C. Luk, John Q. Trojanowski, Virginia M. Y. Lee, Wendy Noble, Raymond C. C. Chang
Summary: This study investigates the role of pathological alpha-synuclein in Parkinson's disease. The results suggest that spread/replication of pathological aSyn may not be sufficient to induce neurodegenerative changes. Instead, oxidative stress responses and aSyn accumulation are associated with other Parkinson's disease-associated abnormalities and cognitive dysfunction.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Paula Beltran-Lobo, Matthew J. Reid, Maria Jimenez-Sanchez, Alexei Verkhratsky, Beatriz G. Perez-Nievas, Wendy Noble
Summary: Astrocytes play important roles in maintaining the balance and defense of the central nervous system. In Alzheimer's disease, astrocytes undergo various changes and are closely associated with abnormal protein aggregates. This review focuses on the P2X7 receptor and its contribution to altered astrocyte functions in Alzheimer's disease. Animal studies have shown that targeting P2X7 receptor can improve cognitive and synaptic impairments in models of the disease.
ESSAYS IN BIOCHEMISTRY
(2023)
Review
Clinical Neurology
Sarah J. Marzi, Brian M. Schilder, Alexi Nott, Carlo Sala Frigerio, Sandrine Willaime-Morawek, Magda Bucholc, Diane P. Hanger, Charlotte James, Patrick A. Lewis, Ilianna Lourida, Wendy Noble, Francisco Rodriguez-Algarra, Jalil-Ahmad Sharif, Maria Tsalenchuk, Laura M. Winchester, Umran Yaman, Zhi Yao, Janice M. Ranson, David J. Llewellyn
Summary: This article reviews the application of artificial intelligence (AI) and machine learning (ML) in dementia research. The challenges of reproducibility and cross-species translation are discussed, and the potential of AI and ML methods to enhance research and translation is evaluated. Data resources and AI approaches are highlighted as solutions, and the exciting future possibilities of multi-omics analysis with AI in drug discovery are mentioned.
ALZHEIMERS & DEMENTIA
(2023)
Article
Clinical Neurology
Elizabeth B. Glennon, Dawn H. W. Lau, Rebecca M. C. Gabriele, Matthew F. Taylor, Claire Troakes, Sarah Opie-Martin, Christina Elliott, Richard Killick, Diane P. Hanger, Beatriz G. Perez-Nievas, Wendy Noble
BRAIN COMMUNICATIONS
(2020)