The Significance of Tau Aggregates in the Human Brain
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Basal Forebrain Volume Reliably Predicts the Cortical Spread of Alzheimer’S Degeneration
bioRxiv preprint doi: https://doi.org/10.1101/676544; this version posted June 20, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Title: Basal forebrain volume reliably predicts the cortical spread of Alzheimer’s degeneration Short running title: Predictive spread of Alzheimer’s degeneration Authors: Sara Fernández-Cabello1,2, Martin Kronbichler1,2,3, Koene R. A. Van Dijk4, James A. Goodman4, R. Nathan Spreng5,6,7, Taylor W. Schmitz8,9 for the Alzheimer’s Disease Neuroimaging Initiative* Affiliations: 1 Department of Psychology, University of Salzburg, Salzburg, Austria 2 Centre for Cognitive Neuroscience, University of Salzburg, Salzburg, Austria 3 Neuroscience Institute, Christian-Doppler Medical Centre, Paracelsus Medical University, Salzburg, Austria. 4 Clinical and Translational Imaging, Early Clinical Development, Pfizer Inc, Cambridge, MA, United States 5 Laboratory of Brain and Cognition, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada 6 Departments of Psychiatry and Psychology, McGill University, Montreal, QC, Canada 7 Douglas Mental Health University Institute, Verdun, QC, Canada 8 Brain and Mind Institute, Western University, London, ON, Canada 9 Department of Physiology and Pharmacology, Western University, London, ON, Canada * Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. -
The Prion-Like Spreading of Alpha-Synuclein in Parkinson’S Disease: Update on Models and Hypotheses
International Journal of Molecular Sciences Review The Prion-Like Spreading of Alpha-Synuclein in Parkinson’s Disease: Update on Models and Hypotheses Asad Jan 1,* ,Nádia Pereira Gonçalves 1,2 , Christian Bjerggaard Vaegter 1,2 , Poul Henning Jensen 1 and Nelson Ferreira 1,* 1 Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; [email protected] (N.P.G.); [email protected] (C.B.V.); [email protected] (P.H.J.) 2 International Diabetic Neuropathy Consortium (IDNC), Aarhus University Hospital, 8200 Aarhus, Denmark * Correspondence: [email protected] (A.J.); [email protected] (N.F.) Abstract: The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propa- gation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson’s disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of en- dogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of mis- folded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic Citation: Jan, A.; Gonçalves, N.P.; intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic Vaegter, C.B.; Jensen, P.H.; Ferreira, N. -
(Brainnet Europe Protocol) to the MRC Cognitive Function and Ageing Brain Study Stephen B
Wharton et al. Acta Neuropathologica Communications (2016) 4:11 DOI 10.1186/s40478-016-0275-x RESEARCH Open Access Epidemiological pathology of Tau in the ageing brain: application of staging for neuropil threads (BrainNet Europe protocol) to the MRC cognitive function and ageing brain study Stephen B. Wharton1, Thais Minett2,3, David Drew1, Gillian Forster1, Fiona Matthews4, Carol Brayne3, Paul G. Ince1* and on behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group Abstract Introduction: Deposition of abnormally phosphorylated tau (phospho-tau) occurs in Alzheimer’sdisease but also with brain ageing. The Braak staging scheme focused on neurofibrillary tangles, butabundant p-tau is also present in neuropil threads, and a recent scheme has been proposed by theBrainNet Europe consortium for staging tau pathology based on neuropil threads. We determined therelationship of threads to tangles, and the value of staging for threads in an unselected population-representative ageing brain cohort. We also determined the prevalence of astroglial tau pathologies, and their relationship to neuronal tau. Phospho-tau pathology was determined by immunohistochemistry (AT8 antibody) in the MRC-CFAS neuropathology cohort. Neuropil threads were staged using the BrainNet Europe protocol for tau pathology, and compared with Braak tangle stages. Astroglial tau pathology was assessed in neo-cortical, mesial temporal and subcortical areas. Results: Cases conformed well to the hierarchical neuropil threads staging of the BrainNet Europe protocol and correlated strongly with Braak staging (r=0.84, p < 0.001). Based on the areas under the receiver operator curves (AUC), incorporating either threads or tangle staging significantly improved dementia case identification to a similar degree over age alone (Braak stage X2(1)=10.1, p=0.002; BNE stage X2(1)=9.7, p=0.002). -
Pathologic Thr175 Tau Phosphorylation in CTE and CTE with ALS
Published Ahead of Print on January 3, 2018 as 10.1212/WNL.0000000000004899 ARTICLE OPEN ACCESS Pathologic Thr175 tau phosphorylation in CTE and CTE with ALS Alexander J. Moszczynski, PhD, Wendy Strong, BSc, Kathy Xu, MSc, Ann McKee, MD, Arthur Brown, PhD, Correspondence and Michael J. Strong, MD Dr. M.J. Strong [email protected] Neurology® 2018;90:e1-8. doi:10.1212/WNL.0000000000004899 Abstract Objective To investigate whether chronic traumatic encephalopathy (CTE) and CTE with amyotrophic lateral sclerosis (CTE-ALS) exhibit features previously observed in other tauopathies of pathologic phosphorylation of microtubule-associated protein tau at Thr175 (pThr175 tau) and Thr231 (pThr231 tau), and glycogen synthase kinase–3β (GSK3β) activation, and whether these pathologic features are a consequence of traumatic brain injury (TBI). Methods Tau isoform expression was assayed by western blot in 6 stage III CTE cases. We also used immunohistochemistry to analyze 5 cases each of CTE, CTE-ALS, and 5 controls for ex- pression of activated GSK3β, pThr175 tau, pThr231 tau, and oligomerized tau within spinal cord tissue and hippocampus. Using a rat model of moderate TBI, we assessed tau pathology and phospho-GSK3β expression at 3 months postinjury. Results CTE and CTE-ALS are characterized by the presence of all 6 tau isoforms in both soluble and insoluble tau isolates. Activated GSK3β, pThr175 tau, pThr231 tau, and oligomerized tau protein expression was observed in hippocampal neurons and spinal motor neurons. We observed tau neuronal pathology (fibrillar inclusions and axonal damage) and increased levels of pThr175 tau and activated GSK3β in moderate TBI rats. Conclusions Pathologic phosphorylation of tau at Thr175 and Thr231 and activation of GSK3β are features of the tauopathy of CTE and CTE-ALS. -
Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies
cells Review Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies Inês C. Brás 1 and Tiago F. Outeiro 1,2,3,4,* 1 Center for Biostructural Imaging of Neurodegeneration, Department of Experimental Neurodegeneration, University Medical Center Göttingen, 37075 Göttingen, Germany; [email protected] 2 Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany 3 Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK 4 Scientific Employee with a Honorary Contract at Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 37075 Göttingen, Germany * Correspondence: [email protected]; Tel.: +49-(0)-551-391-3544; Fax: +49-(0)-551-392-2693 Abstract: The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson’s disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clin- ically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding Citation: Brás, I.C.; Outeiro, T.F. -
Elucidating Crosstalk Mechanisms Between Phosphorylation and O
Elucidating crosstalk mechanisms between PNAS PLUS phosphorylation and O-GlcNAcylation Aneika C. Leneya,b,c,d, Dris El Atmiouie, Wei Wua,b,c,d, Huib Ovaae, and Albert J. R. Hecka,b,c,d,1 aBiomolecular Mass Spectrometry and Proteomics, Utrecht University, 3584 CH Utrecht, The Netherlands; bBijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands; cUtrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, The Netherlands; dNetherlands Proteomics Centre, Utrecht University, 3584 CH Utrecht, The Netherlands; and eChemical Immunology, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands Edited by Tony Hunter, The Salk Institute for Biological Studies, La Jolla, CA, and approved July 21, 2017 (received for review December 14, 2016) Proteins can be modified by multiple posttranslational modifications from studies in which cellular stimuli were shown to increase both (PTMs), creating a PTM code that controls the function of proteins in O-GlcNAcylation and phosphorylation levels simultaneously (6, 7). space and time. Unraveling this complex PTM code is one of the great Although, many studies have demonstrated that crosstalk occurs, challenges in molecular biology. Here, using mass spectrometry-based studies that identify and colocalize both the phosphorylation and assays, we focus on the most common PTMs—phosphorylation and O-GlcNAcylation sites simultaneously on the same protein/peptide O-GlcNAcylation—and investigate how they affect each other. We are sporadic. Thus, doubt still exists as to whether on a specific demonstrate two generic crosstalk mechanisms. First, we define a protein molecule O-GlcNAcylation directly affects phosphorylation frequently occurring, very specific and stringent phosphorylation/ or vice versa. -
NIH Public Access Author Manuscript J Neuropathol Exp Neurol
NIH Public Access Author Manuscript J Neuropathol Exp Neurol. Author manuscript; available in PMC 2010 September 24. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: J Neuropathol Exp Neurol. 2009 July ; 68(7): 709±735. doi:10.1097/NEN.0b013e3181a9d503. Chronic Traumatic Encephalopathy in Athletes: Progressive Tauopathy following Repetitive Head Injury Ann C. McKee, MD1,2,3,4, Robert C. Cantu, MD3,5,6,7, Christopher J. Nowinski, AB3,5, E. Tessa Hedley-Whyte, MD8, Brandon E. Gavett, PhD1, Andrew E. Budson, MD1,4, Veronica E. Santini, MD1, Hyo-Soon Lee, MD1, Caroline A. Kubilus1,3, and Robert A. Stern, PhD1,3 1 Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 2 Department of Pathology, Boston University School of Medicine, Boston, Massachusetts 3 Center for the Study of Traumatic Encephalopathy, Boston University School of Medicine, Boston, Massachusetts 4 Geriatric Research Education Clinical Center, Bedford Veterans Administration Medical Center, Bedford, Massachusetts 5 Sports Legacy Institute, Waltham, MA 6 Department of Neurosurgery, Boston University School of Medicine, Boston, Massachusetts 7 Department of Neurosurgery, Emerson Hospital, Concord, MA 8 CS Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Abstract Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed “dementia pugilistica” and more recently, chronic traumatic encephalopathy (CTE). We review the 47 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 professional athletes: one football player and 2 boxers. -
The Consequences of Pretangle Tau in the Locus Coeruleus Termpanit Chalermpalanupap, Emory University David Weinshenker, Emory University Jacki M
Down but Not Out: The Consequences of Pretangle Tau in the Locus Coeruleus Termpanit Chalermpalanupap, Emory University David Weinshenker, Emory University Jacki M. Rorabaugh, Emory University Journal Title: Neural Plasticity Volume: Volume 2017 Publisher: Hindawi Publishing Corporation | 2017-09-05, Pages 7829507-7829507 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1155/2017/7829507 Permanent URL: https://pid.emory.edu/ark:/25593/s64c4 Final published version: http://dx.doi.org/10.1155/2017/7829507 Copyright information: © 2017 Termpanit Chalermpalanupap et al. This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). Accessed September 29, 2021 12:12 PM EDT Hindawi Neural Plasticity Volume 2017, Article ID 7829507, 9 pages https://doi.org/10.1155/2017/7829507 Review Article Down but Not Out: The Consequences of Pretangle Tau in the Locus Coeruleus Termpanit Chalermpalanupap, David Weinshenker, and Jacki M. Rorabaugh Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA Correspondence should be addressed to Jacki M. Rorabaugh; [email protected] Received 10 March 2017; Revised 20 June 2017; Accepted 20 July 2017; Published 5 September 2017 Academic Editor: Niels Hansen Copyright © 2017 Termpanit Chalermpalanupap et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Degeneration of locus coeruleus (LC) is an underappreciated hallmark of Alzheimer’s disease (AD). The LC is the main source of norepinephrine (NE) in the forebrain, and its degeneration is highly correlated with cognitive impairment and amyloid-beta (Aβ) and tangle pathology. -
The Unfolded Protein Response Is Activated in the Olfactory System in Alzheimer’S Disease Helen C
Murray et al. Acta Neuropathologica Communications (2020) 8:109 https://doi.org/10.1186/s40478-020-00986-7 RESEARCH Open Access The unfolded protein response is activated in the olfactory system in Alzheimer’s disease Helen C. Murray1,2* , Birger Victor Dieriks1, Molly E. V. Swanson1, Praju Vikas Anekal1, Clinton Turner3, Richard L. M. Faull1, Leonardo Belluscio4, Alan Koretsky2 and Maurice A. Curtis1* Abstract Olfactory dysfunction is an early and prevalent symptom of Alzheimer’s disease (AD) and the olfactory bulb is a nexus of beta-amyloid plaque and tau neurofibrillary tangle (NFT) pathology during early AD progression. To mitigate the accumulation of misfolded proteins, an endoplasmic reticulum stress response called the unfolded protein response (UPR) occurs in the AD hippocampus. However, chronic UPR activation can lead to apoptosis and the upregulation of beta-amyloid and tau production. Therefore, UPR activation in the olfactory system could be one of the first changes in AD. In this study, we investigated whether two proteins that signal UPR activation are expressed in the olfactory system of AD cases with low or high amounts of aggregate pathology. We used immunohistochemistry to label two markers of UPR activation (p-PERK and p-eIF2α) concomitantly with neuronal markers (NeuN and PGP9.5) and pathology markers (beta-amyloid and tau) in the olfactory bulb, piriform cortex, entorhinal cortex and the CA1 region of the hippocampus in AD and normal cases. We show that UPR activation, as indicated by p-PERK and p-eIF2α expression, is significantly increased throughout the olfactory system in AD cases with low (Braak stage III-IV) and high-level (Braak stage V-VI) pathology. -
Immune Effector Mechanisms and Designer Vaccines Stewart Sell Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY, USA
EXPERT REVIEW OF VACCINES https://doi.org/10.1080/14760584.2019.1674144 REVIEW How vaccines work: immune effector mechanisms and designer vaccines Stewart Sell Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY, USA ABSTRACT ARTICLE HISTORY Introduction: Three major advances have led to increase in length and quality of human life: Received 6 June 2019 increased food production, improved sanitation and induction of specific adaptive immune Accepted 25 September 2019 responses to infectious agents (vaccination). Which has had the most impact is subject to debate. KEYWORDS The number and variety of infections agents and the mechanisms that they have evolved to allow Vaccines; immune effector them to colonize humans remained mysterious and confusing until the last 50 years. Since then mechanisms; toxin science has developed complex and largely successful ways to immunize against many of these neutralization; receptor infections. blockade; anaphylactic Areas covered: Six specific immune defense mechanisms have been identified. neutralization, cytolytic, reactions; antibody- immune complex, anaphylactic, T-cytotoxicity, and delayed hypersensitivity. The role of each of these mediated cytolysis; immune immune effector mechanisms in immune responses induced by vaccination against specific infectious complex reactions; T-cell- mediated cytotoxicity; agents is the subject of this review. delayed hypersensitivity Expertopinion: In the past development of specific vaccines for infections agents was largely by trial and error. With an understanding of the natural history of an infection and the effective immune response to it, one can select the method of vaccination that will elicit the appropriate immune effector mechanisms (designer vaccines). These may act to prevent infection (prevention) or eliminate an established on ongoing infection (therapeutic). -
Investigation of Anti-Iglon5-Induced Neurodegenerative Changes in Human Neurons
bioRxiv preprint doi: https://doi.org/10.1101/2020.08.27.269795; this version posted August 28, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Manuscript BioRxiv Investigation of anti-IgLON5-induced neurodegenerative changes in human neurons Mattias Gamre1,2, Matias Ryding1,2, Mette Scheller Nissen1,2,3, Anna Christine Nilsson4, Morten Meyer1,2,5, Morten Blaabjerg1,2,3,5 1Neurobiological Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. 2Department of Neurology, Odense University Hospital, Odense, Odense, Denmark 3Department of Clinical Research, Odense University Hospital, Odense, Denmark 4Department of Clinical Immunology, Odense University Hospital, Odense, Denmark 5BRIDGE – Brain Research Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark Number of pages: 12 Number of figures: 4 Keywords: IgLON5, Autoimmune encephalitis, neurodegeneration, inflammation, Tau Corresponding author Professor Morten Blaabjerg, MD, PhD Department of Neurology Odense University Hospital J.B. Winsløws Vej 4 5000 Odense C Denmark Phone: (+45) 6541 2457 E-mail: [email protected] Page 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.27.269795; this version posted August 28, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. -
Aluminum Neurotoxicity — Potential Role in the Pathogenesis of Neurofibrillary Tangle Formation Daniel P
LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES Aluminum Neurotoxicity — Potential Role in the Pathogenesis of Neurofibrillary Tangle Formation Daniel P. Perl and William W. Pendlebury ABSTRACT: Alzheimer's disease is a progressive neurodegenerative disease characterized neuropathologically by the development of large numbers of neurofibrillary tangles in certain neuronal populations of affected brains. This paper presents a review of the available evidence which suggests that aluminum is associated with Alzheimer's disease and specifically with the development of the neurofibrillary tangle. Aluminum salts innoculated into experi mental animals produce neurofilamentous lesions which are similar, though not identical, to the neurofibrillary tangle of man. Although a few reports have suggested evidence of increased amounts of aluminum in the brains of Alzheimer's disease victims, such bulk analysis studies have been difficult to replicate. Using scanning electron microscopy with x-ray spectrometry, we have identified accumulations of aluminum in neurofibrillary tangle-bearing neurons of Alzheimer's disease. Similar accumulations have been identified in the neurofibrillary tangle-bearing neurons found in the brains of indigenous natives of Guam who suffer from parkinsonism with dementia and amyotrophic lateral sclerosis. This ongoing research still cannot ascribe a causal role of aluminum in the pathogenesis of neurofibrillary tangle formation; however, it does suggest that environmental factors may play an important part in the formation of this abnormality. RESUME: La neurotoxicity de Paluminium: son role possible dans la pathogenese de la formation des enchevetrements neurofibrillaires. La maladie d'Alzheimer est une maladie neurodegenerative progressive caracterisee au point de vue anatomo-pathologique par le developpement d'un grand nombre d'enchevetrements neurofibrillaires au sein de certaines populations de neurones dans le cerveau des sujets atteints.