Phosphorylated tau interactome in the human Alzheimer’s disease brain DOI Open Access
Eleanor Drummond, Geoffrey Pires, Claire MacMurray

et al.

Brain, Journal Year: 2020, Volume and Issue: 143(9), P. 2803 - 2817

Published: June 23, 2020

Accumulation of phosphorylated tau is a key pathological feature Alzheimer's disease. Phosphorylated accumulation causes synaptic impairment, neuronal dysfunction and formation neurofibrillary tangles. The actions are mediated by surrounding proteins; however, comprehensive understanding the proteins that interacts with in disease surprisingly limited. Therefore, aim this study was to determine interactome. To end, we used two complementary proteomics approaches: (i) quantitative performed on tangles microdissected from patients advanced disease; (ii) affinity purification-mass spectrometry identify which these specifically bound tau. We identified 542 This included abundant detection many known be present such as tau, ubiquitin, neurofilament apolipoprotein E. Affinity confirmed 75 interacted PHF1-immunoreactive Twenty-nine have been previously associated therefore validating our proteomic approach. More importantly, 34 had total but not yet linked directly (e.g. protein VAMP2, vacuolar-ATPase subunit ATP6V0D1); therefore, provide new evidence they interact In addition, also 12 novel proteins, physiologically or pathologically RNA binding HNRNPA1). Network analysis showed interactome enriched involved ubiquitination pathway phagosome maturation. Importantly, were able pinpoint specific pathways for first time, providing potential pathogenic mechanisms can explored future studies. Combined, results reveal drug targets treatment tauopathies insight into how mediates its toxicity

Language: Английский

Tau in physiology and pathology DOI
Yipeng Wang, Eckhard Mandelkow�

Nature reviews. Neuroscience, Journal Year: 2015, Volume and Issue: 17(1), P. 22 - 35

Published: Dec. 3, 2015

Language: Английский

Citations

1779
Pathology of Neurodegenerative Diseases DOI Open Access
Brittany N. Dugger, Dennis W. Dickson

Cold Spring Harbor Perspectives in Biology, Journal Year: 2017, Volume and Issue: 9(7), P. a028035 - a028035

Published: Jan. 6, 2017

Brittany N. Dugger1 and Dennis W. Dickson2 1Institute for Neurodegenerative Diseases, Department of Neurology, Weill Institute Neurosciences, University California, San Francisco, California 94143 2Mayo Clinic, Jacksonville, Florida 32224 Correspondence: brittany.dugger{at}ucsf.edu

Language: Английский

Citations

1300
Neuronal Cell Death DOI Open Access
Michael Fricker, Aviva M. Tolkovsky, Vilmantė Borutaitė

et al.

Physiological Reviews, Journal Year: 2018, Volume and Issue: 98(2), P. 813 - 880

Published: Feb. 28, 2018

Neuronal cell death occurs extensively during development and pathology, where it is especially important because of the limited capacity adult neurons to proliferate or be replaced. The concept used simple as there were just two three types, so we had work out which type was involved in our particular pathology then block it. However, now know that are at least a dozen ways for die, blocking mechanism may not prevent from dying, non-neuronal cells also contribute neuronal death. We review here mechanisms by intrinsic extrinsic apoptosis, oncosis, necroptosis, parthanatos, ferroptosis, sarmoptosis, autophagic death, autosis, autolysis, paraptosis, pyroptosis, phagoptosis, mitochondrial permeability transition. next explore development, those induced axotomy, aberrant cell-cycle reentry, glutamate (excitoxicity oxytosis), loss connected neurons, aggregated proteins unfolded protein response, oxidants, inflammation, microglia. reassess forms occur stroke Alzheimer’s disease, most pathologies involving discuss why has been difficult pinpoint involved, if matters, molecular overlap interplay between subroutines, therapeutic implications these multiple overlapping

Language: Английский

Citations

936
Network abnormalities and interneuron dysfunction in Alzheimer disease DOI
Jorge J. Palop, Lennart Mucke

Nature reviews. Neuroscience, Journal Year: 2016, Volume and Issue: 17(12), P. 777 - 792

Published: Nov. 10, 2016

Language: Английский

Citations

825
Roles of tau protein in health and disease DOI Creative Commons
Tong Guo, Wendy Noble, Diane P. Hanger

et al.

Acta Neuropathologica, Journal Year: 2017, Volume and Issue: 133(5), P. 665 - 704

Published: April 6, 2017

Tau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates accompanied by synaptic dysfunction and neural cell death range neurodegenerative disorders, collectively referred to tauopathies. Recent advances our understanding the multiple functions different locations inside outside neurons have revealed novel insights its importance diverse molecular pathways including signalling, plasticity, regulation genomic stability. The present review describes physiological pathophysiological properties how these relate distribution We highlight post-translational modifications tau, which are pivotal defining modulating localisation roles health disease. include discussion other pathologically relevant changes mutation aggregation, aspects impinge on propensity propagate, potentially drive neuronal loss, diseased brain. Finally, we describe cascade events that may be driven dysfunction, impaired axonal transport, alterations synapse mitochondrial function, activation unfolded response defective degradation. It important fully understand attributed since this will provide vital information involvement development pathogenesis Such knowledge enable determination critical should targeted potential therapeutic agents developed for treatment

Language: Английский

Citations

821
The Neuropathology and Neurobiology of Traumatic Brain Injury DOI Creative Commons
Kaj Blennow, John Hardy, Henrik Zetterberg

et al.

Neuron, Journal Year: 2012, Volume and Issue: 76(5), P. 886 - 899

Published: Dec. 1, 2012

Language: Английский

Citations

623
The release and trans-synaptic transmission of Tau via exosomes DOI Creative Commons
Yipeng Wang,

Varun Balaji,

Senthilvelrajan Kaniyappan

et al.

Molecular Neurodegeneration, Journal Year: 2017, Volume and Issue: 12(1)

Published: Jan. 13, 2017

Tau pathology in AD spreads a hierarchical pattern, whereby it first appears the entorhinal cortex, then to hippocampus and later surrounding areas. Based on this sequential appearance, can be classified into six stages ("Braak stages"). The mechanisms agents underlying progression of are matter debate. Emerging evidence indicates that propagation may due transmission protein, but pathways species not well understood. In study we investigated question spreading via small extracellular vesicles called exosomes.Exosomes from different sources were analyzed by biochemical methods electron microscopy (EM) cryo-EM. Microfluidic devices allow culture cell populations compartments used investigate Tau.We show protein is released cultured primary neurons or N2a cells overexpressing constructs exosomes. Neuron-derived exosomal hypo-phosphorylated, compared with cytosolic Tau. Depolarization promotes release Tau-containing exosomes, highlighting importance neuronal activity. Using microfluidic exosomes mediate trans-neuronal transfer depending synaptic connectivity. achieved direct between neurons. organotypic hippocampal slices, conditioned medium taken up microglia, astrocytes. cells, assemblies They induce inclusions other molecules expressing mutant human We also studied cerebrospinal fluid control subjects containing monomeric oligomeric Split-luciferase complementation reveals CSF promote aggregation cells.Our demonstrates contribute trans-synaptic transmission, thus offer new approches tauopathies.

Language: Английский

Citations

587
Anti-Tau Antibodies that Block Tau Aggregate Seeding In Vitro Markedly Decrease Pathology and Improve Cognition In Vivo DOI Creative Commons
Kiran Yanamandra, Najla Kfoury, Hong Jiang

et al.

Neuron, Journal Year: 2013, Volume and Issue: 80(2), P. 402 - 414

Published: Sept. 26, 2013

Language: Английский

Citations

542
Tau and tauopathies DOI
Thomas Arendt, Jens Stieler, Max Holzer

et al.

Brain Research Bulletin, Journal Year: 2016, Volume and Issue: 126, P. 238 - 292

Published: Sept. 1, 2016

Language: Английский

Citations

520
Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease DOI Open Access
Colin L. Masters,

D. J. Selkoe

Cold Spring Harbor Perspectives in Medicine, Journal Year: 2012, Volume and Issue: 2(6), P. a006262 - a006262

Published: Feb. 21, 2012

Colin L. Masters1 and Dennis J. Selkoe2 The Mental Health Research Institute, University of Melbourne, Parkville 3010, Australia Center for Neurologic Diseases, Harvard Medical School Brigham Women's Hospital, Boston, Massachusetts 02115 Correspondence: c.masters{at}unimelb.edu.au

Language: Английский

Citations

503