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
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)
Article
Clinical Neurology
Bryce A. Mander, Abhishek Dave, Kitty K. Lui, Katherine E. Sprecher, Destiny Berisha, Miranda G. Chappel-Farley, Ivy Y. Chen, Brady A. Riedner, Margo Heston, Ivonne Suridjan, Gwendlyn Kollmorgen, Henrik Zetterberg, Kaj Blennow, Cynthia M. Carlsson, Ozioma C. Okonkwo, Sanjay Asthana, Sterling C. Johnson, Barbara B. Bendlin, Ruth M. Benca
Summary: The study found an association between fast sleep spindle deficits and biomarkers of Alzheimer's disease in cognitively unimpaired older adults. Age indirectly affected fast sleep spindle expression through microglial activation markers, tau phosphorylation, and synaptic degeneration markers. Sleep spindle expression was also associated with overnight memory retention. The findings suggest that microglia dysfunction is related to memory impairment and may serve as a promising therapeutic target to prevent cognitive decline.
Article
Clinical Neurology
Leticia Peris, Julie Parato, Xiaoyi Qu, Jean-Marc Soleilhac, Fabien Lante, Atul Kumar, Maria Elena Pero, Jose Martinez-Hernandez, Charlotte Corrao, Giulia Falivelli, Floriane Payet, Sylvie Gory-Faure, Christophe Bosc, Marian Blanca Ramirez, Andrew Sproul, Jacques Brocard, Benjamin Di Cara, Philippe Delagrange, Alain Buisson, Yves Goldberg, Marie-Jo Moutin, Francesca Bartolini, Annie Andrieux
Summary: Microtubules are important for neuronal processes, synaptic function, and plasticity. The balance between tubulin tyrosination and detyrosination is crucial for maintaining microtubule dynamics and neuronal homeostasis. This study reveals that decreased tubulin tyrosine ligase expression is associated with Alzheimer's disease and leads to memory impairment and reduced synaptic integrity. Restoring microtubule entry into dendritic spines through tubulin retyrosination can protect against amyloid-beta peptide-induced synaptic damage.
Article
Neurosciences
Yuxing Xia, Brach M. M. Bell, Justin D. D. Kim, Benoit I. I. Giasson
Summary: Tauopathies are neurodegenerative diseases characterized by the formation of tau brain aggregates. Imbalance of 3R and 4R tau isoforms is a contributing factor in the development of these diseases. The S356T tau mutation shows unique prion-like seeded aggregation, forming extensive Thioflavin positive aggregates. This finding will contribute to the understanding of diverse presentations of different tauopathies.
FRONTIERS IN NEUROSCIENCE
(2023)
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)
Article
Biochemistry & Molecular Biology
Hilda Mirbaha, Dailu Chen, Vishruth Mullapudi, Sandi Jo Terpack, Charles L. White, Lukasz A. Joachimiak, Marc Diamond
Summary: The study reveals that the initiation of tauopathy is associated with the formation of seed-competent (M-s) tau monomers, which precedes the formation of insoluble fibrils. This research provides important insights into the origins of tauopathy and highlights the significance of M-s monomers in disease progression.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Hilda Mirbaha, Dailu Chen, Vishruth Mullapudi, Sandi Jo Terpack, Charles L. White, Lukasz A. Joachimiak, Marc Diamond
Summary: The research shows that in a mouse model of tauopathy, the disease begins with the formation of M-s monomers, whose conformational activity is independent of phosphorylation, and forms oligomers before further assembling into insoluble fibrils.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Neurosciences
Francois-Xavier Cantrelle, Anne Loyens, Xavier Trivelli, Oliver Reimann, Clement Despres, Neha S. Gandhi, Christian P. R. Hackenberger, Isabelle Landrieu, Caroline Smet-Nocca
Summary: Phosphorylation of Tau protein plays a critical role in the aggregation process observed in Alzheimer's disease brains. Recent research has highlighted the regulatory role of O-GlcNAcylation in modulating Tau phosphorylation and aggregation. Results showed that O-GlcNAcylation reduces phosphorylation of PHF-1 epitope, which is hyperphosphorylated in AD brains, and impacts the rate of fibrillar assembly in in-vitro assays.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2021)
Article
Clinical Neurology
Luis Aragao Gomes, Valerie Uytterhoeven, Diego Lopez-Sanmartin, Sandra O. Tome, Thomas Tousseyn, Rik Vandenberghe, Mathieu Vandenbulcke, Christine A. F. von Arnim, Patrik Verstreken, Dietmar Rudolf Thal
Summary: In the study, tau pathology initiation in Alzheimer's disease was found to follow similar processes when propagating into previously unaffected regions, with the appearance of IC- and IN-tau being the initial tau lesions. This suggests that these lesions may play a crucial role in the development of Alzheimer's disease, even in cases classified as nonAD.
ACTA NEUROPATHOLOGICA
(2021)
Article
Clinical Neurology
Kanta Horie, Nicolas R. Barthelemy, Chihiro Sato, Randall J. Bateman
Summary: The study analyzed MTBR-Tau species in Alzheimer's disease and control CSF using sequential immunoprecipitation and chemical extraction methods followed by mass spectrometry. The species containing the region beginning at residue 243 were found to be highly correlated with tau PET and cognitive measures. This suggests that CSF level of tau species containing the upstream region of MTBR may serve as biomarkers to stage Alzheimer's disease and track the development of tau-directed therapeutics.
Article
Clinical Neurology
Kanta Horie, Nicolas R. Barthelemy, Chihiro Sato, Randall J. Bateman
Summary: The study analyzed MTBR-tau species in CSF and found that tau species containing the upstream region of MTBR were highly correlated with tau PET and cognitive assessments in Alzheimer's disease, suggesting they could serve as biomarkers for staging Alzheimer's disease and tracking tau-directed therapeutics development.
Article
Cell Biology
Xing Jun Jiang, Yan Qing Wu, Rong Ma, Yan Min Chang, Lu Lu Li, Jia Hui Zhu, Gong Ping Liu, Gang Li
Summary: This study found that overexpression of PINK1 can promote the degradation of accumulated tau proteins in patients with AD, improving cognitive abilities and rescuing damaged neurons and synapses. Furthermore, PINK1 also improves mitochondrial dysfunction caused by tau proteins. This suggests that PINK1 may be a potential target for AD treatment.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Clinical Neurology
Zhi Ruan, Dhruba Pathak, Srinidhi Venkatesan Kalavai, Asuka Yoshii-Kitahara, Satoshi Muraoka, Nemil Bhatt, Kayo Takamatsu-Yukawa, Jianqiao Hu, Yuzhi Wang, Samuel Hersh, Maria Ericsson, Santhi Gorantla, Howard E. Gendelman, Rakez Kayed, Seiko Ikezu, Jennifer Luebke, Tsuneya Ikezu
Summary: This study comprehensively characterized the physicochemical structure and pathogenic function of extracellular vesicles derived from human brains in Alzheimer's disease, prodromal Alzheimer's disease, and non-demented control cases. It was found that extracellular vesicles from Alzheimer's disease cases had higher levels of tau oligomers and exhibited more efficient propagation and misfolding of tau, suggesting a novel mechanism for tau spread in the hippocampus.
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)
Article
Biochemistry & Molecular Biology
Anne Nitsche, Christian Arnold, Uwe Ueberham, Kristin Reiche, Joerg Fallmann, Joerg Hackermueller, Friedemann Horn, Peter F. Stadler, Thomas Arendt
Summary: Alzheimer's disease is a neurodegenerative disorder that predominantly affects elderly humans, with little occurrence in non-primate mammals and non-human primates. Research shows that most AD-associated genes have ancient evolutionary origins, but exhibit faster gene structure evolution in loci with AD-related expression changes. Particularly, non-coding genes associated with AD play a significant role in the disease.
MOLECULAR PSYCHIATRY
(2021)
Article
Neurosciences
Sophie Schmidt, Caroline Stapf, Sandra Schmutzler, Ingolf Lachmann, Thomas Arendt, Max Holzer, Mandy Sonntag, Markus Morawski
Summary: Selected neurons in the central nervous system are surrounded by perineuronal nets (PNs) which regulate plasticity and synaptic physiology. Research showed that aggrecan, a component of PNs, has a neuroprotective role by preventing internalization of pathological tau forms. However, in a mouse model, reduced aggrecan levels led to increased tau protein and phosphorylation, suggesting a correlation between aggrecan and tau pathology triggered by mutation.
EUROPEAN JOURNAL OF NEUROSCIENCE
(2021)
Article
Cell Biology
Miguel Portillo, Ekaterina Eremenko, Shai Kaluski, Alfredo Garcia-Venzor, Lior Onn, Daniel Stein, Zeev Slobodnik, Adam Zaretsky, Uwe Ueberham, Monica Einav, Martina K. Brueckner, Thomas Arendt, Debra Toiber
Summary: Tau protein hyper-acetylation at residue 174 increases its nuclear presence and is related to DNA damage signaling or lack of SIRT6, both causative of neurodegeneration. This leads to global changes in gene expression, affecting protein synthesis and energy production. AD patients show increased levels of nuclear Tau-K174ac, potentially due to DNA damage signaling and SIRT6 depletion.
Article
Neurosciences
I. Friedrich, K. Reimann, S. Jankuhn, E. Kirilina, J. Stieler, M. Sonntag, J. Meijer, N. Weiskopf, T. Reinert, T. Arendt, M. Morawski
Summary: Iron is essential for neurons and glial cells but high concentrations of free iron can be detrimental, especially in neurodegenerative diseases. Changes in iron concentrations in the substantia nigra may play a key role in degeneration of dopaminergic neurons in Parkinson's disease. Quantitative analysis of iron provides insights into cellular iron levels in PD.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Anja Reinert, Tilo Reinert, Thomas Arendt, Markus Morawski
Summary: A subpopulation of neurons, characterized by a special extracellular matrix composition forming a perineuronal net (PN) with a high affinity to iron, is less vulnerable to iron-induced oxidative stress and neurodegeneration. These PN+ neurons have higher intracellular iron concentrations and increased levels of iron proteins, with the iron concentration of the PN itself not being increased. The properties of these resilient pacemaker neurons with bustling iron metabolism and outstanding iron handling capabilities contribute to their low vulnerability to iron-induced oxidative stress and degeneration.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Henriette Rusch, Malte Brammerloh, Jens Stieler, Mandy Sonntag, Siawoosh Mohammadi, Nikolaus Weiskopf, Thomas Arendt, Evgeniya Kirilina, Markus Morawski
Summary: The accessibility of new wide-scale multimodal imaging techniques has led to the emergence of numerous tissue clearing techniques. This study compares seven different tissue clearing approaches for aged human brain tissue blocks (>5 mm) to identify the most practical and efficient method. The results show that combining the CLARITY or iDISCO techniques with specific imaging setups is the best approach for clearing aged human brain tissue and generating 3D microscopic images.
Article
Neurosciences
Malte Brammerloh, Markus Morawski, Isabel Friedrich, Tilo Reinert, Charlotte Lange, Primoz Pelicon, Primoz Vavpetic, Steffen Jankuhn, Carsten Jaeger, Anneke Alkemade, Rawien Balesar, Kerrin Pine, Filippos Gavriilidis, Robert Trampel, Enrico Reimer, Thomas Arendt, Nikolaus Weiskopf, Evgeniya Kirilina
Summary: In Parkinson's disease, monitoring the depletion of iron-rich dopaminergic neurons in nigrosome 1 with MRI could serve as a potential biomarker for early diagnosis.
Article
Biochemistry & Molecular Biology
Christian Conze, Marina Rierola, Nataliya Trushina, Michael Peters, Dennis Janning, Max Holzer, Jurgen J. Heinisch, Thomas Arendt, Lidia Bakota, Roland Brandt
Summary: Tau protein plays a central role in diseases like Alzheimer's, and its function can be affected by cellular senescence. In this study, researchers found that a specific form of tau protein (TauC3) is increased in senescent mice and AD patients. This modified tau protein has reduced dynamics in interacting with microtubules, which leads to defects in axonal transport and neuronal degeneration. The microtubule-targeting drug Epothilone D can normalize this interaction and modulate transport processes. These findings suggest the potential of using microtubule-targeting drugs to restore the physiological function of tau protein.
MOLECULAR PSYCHIATRY
(2022)
Article
Biochemistry & Molecular Biology
Sophie Schmidt, Max Holzer, Thomas Arendt, Mandy Sonntag, Markus Morawski
Summary: Tau mutations promote the formation of tau oligomers and filaments, while certain types of neurons are spared of tau pathology due to the protective function of perineuronal nets (PNs), which prevent the internalization of misfolded tau. The study demonstrates a complex interrelation between tau and the proteoglycans of the PN, suggesting that tau can regulate the structure and protein expression of PNs.
Article
Chemistry, Medicinal
Ansgar Opitz, Lisa-Marie Seitz, Vladimir Krystof, Fady Baselious, Max Holzer, Wolfgang Sippl, Andreas Hilgeroth
Summary: In this study, novel compounds were evaluated for their inhibition of protein kinases relevant to Alzheimer's disease, and benzopyridofuranes and naphthopyridofuranes were found to have the best activities.
FUTURE MEDICINAL CHEMISTRY
(2022)
Article
Neurosciences
Zeliha Gozde Turan, Vincent Richter, Jana Bochmann, Poorya Parvizi, Etka Yapar, Ulas Isildak, Sarah-Kristin Waterholter, Sabrina Leclere-Turbant, Cagdas Devrim Son, Charles Duyckaerts, Idil Yet, Thomas Arendt, Mehmet Somel, Uwe Ueberham
Summary: The possible role of somatic copy number variations (CNVs) in Alzheimer's disease (AD) has been controversial. A new study using single-cell whole-genome sequencing (scWGS) readdressed this issue and found slightly higher frequencies of CNV events in cells from AD patients compared to controls, though the differences were not statistically significant. Additionally, cells isolated via laser capture microdissection (LCM) showed higher within-cell read depth variation compared to cells isolated with fluorescence activated cell sorting (FACS).
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2022)
Article
Clinical Neurology
Stephan Steinke, Toni Kirmann, Eleonora A. Loi, Jana Nerlich, Iron Weichard, Philipp Kuhn, Torsten Bullmann, Andreas Ritzau-Jost, Filiz Sila Rizalar, Harald Pruess, Volker Haucke, Christian Geis, Michael Hust, Stefan Hallermann
Summary: Researchers developed and validated a construct that can neutralize autoantibodies from patients with NMDAR encephalitis, preventing receptor internalization and memory deficits in a mouse model. This approach offers a promising strategy for fast and specific treatment of NMDAR encephalitis.
Meeting Abstract
Physiology
T. Bullmann, A. Ritzau-Jost, T. Kaas, A. Woehner, T. Kirmann, F. S. Rizalar, M. Holzer, J. Nerlich, C. Geis, J. -K. Eilers, R. J. Kittel, T. Arendt, V. Haucke, S. Hallermann