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Acta Neuropathologica Communications

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https://www.readbyqxmd.com/read/28086964/anti-%C3%AE-synuclein-immunotherapy-reduces-%C3%AE-synuclein-propagation-in-the-axon-and-degeneration-in-a-combined-viral-vector-and-transgenic-model-of-synucleinopathy
#1
Brian Spencer, Elvira Valera, Edward Rockenstein, Cassia Overk, Michael Mante, Anthony Adame, Wagner Zago, Peter Seubert, Robin Barbour, Dale Schenk, Dora Games, Robert A Rissman, Eliezer Masliah
Neurodegenerative disorders such as Parkinson's Disease (PD), PD dementia (PDD) and Dementia with Lewy bodies (DLB) are characterized by progressive accumulation of α-synuclein (α-syn) in neurons. Recent studies have proposed that neuron-to-neuron propagation of α-syn plays a role in the pathogenesis of these disorders. We have previously shown that antibodies against the C-terminus of α-syn reduce the intra-neuronal accumulation of α-syn and related deficits in transgenic models of synucleinopathy, probably by abrogating the axonal transport and accumulation of α-syn in in vivo models...
January 13, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28077174/mutant-hspb1-causes-loss-of-translational-repression-by-binding-to-pcbp1-an-rna-binding-protein-with-a-possible-role-in-neurodegenerative-disease
#2
Thomas Geuens, Vicky De Winter, Nicholas Rajan, Tilmann Achsel, Ligia Mateiu, Leonardo Almeida-Souza, Bob Asselbergh, Delphine Bouhy, Michaela Auer-Grumbach, Claudia Bagni, Vincent Timmerman
The small heat shock protein HSPB1 (Hsp27) is an ubiquitously expressed molecular chaperone able to regulate various cellular functions like actin dynamics, oxidative stress regulation and anti-apoptosis. So far disease causing mutations in HSPB1 have been associated with neurodegenerative diseases such as distal hereditary motor neuropathy, Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. Most mutations in HSPB1 target its highly conserved α-crystallin domain, while other mutations affect the C- or N-terminal regions or its promotor...
January 11, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28077166/threonine-175-a-novel-pathological-phosphorylation-site-on-tau-protein-linked-to-multiple-tauopathies
#3
Alexander J Moszczynski, Wencheng Yang, Robert Hammond, Lee Cyn Ang, Michael J Strong
Microtubule associated protein tau (tau) deposition is associated with a spectrum of neurodegenerative diseases collectively termed tauopathies. We have previously shown that amyotrophic lateral sclerosis (ALS) with cognitive impairment (ALSci) is associated with tau phosphorylation at Thr(175) and that this leads to activation of GSK3β which then induces phosphorylation at tau Thr(231). This latter step leads to dissociation of tau from microtubules and pathological tau fibril formation. To determine the extent to which this pathway is unique to ALS, we have investigated the expression of pThr(175) tau and pThr(231) tau across a range of frontotemporal degenerations...
January 11, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28073370/expression-site-of-p2ry12-in-residential-microglial-cells-in-astrocytomas-correlates-with-m1-and-m2-marker-expression-and-tumor-grade
#4
Changbin Zhu, Johan M Kros, Marcel van der Weiden, PingPin Zheng, Caroline Cheng, Dana A M Mustafa
The role of resident microglial cells in the pathogenesis and progression of glial tumors is still obscure mainly due to a lack of specific markers. Recently P2RY12, a P2 purinergic receptor, was introduced as a specific marker for microglial cells under normal and pathologic conditions. Here we analyzed the expression of P2RY12 in astrocytomas of various malignancy grades in relation to markers for M1 and M2 macrophage activation profiles by using two web-based glioma datasets and confocal immunohistochemistry to 28 astrocytoma samples grades II-IV...
January 10, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28069058/endosulfine-alpha-inhibits-membrane-induced-%C3%AE-synuclein-aggregation-and-protects-against-%C3%AE-synuclein-neurotoxicity
#5
Daniel Ysselstein, Benjamin Dehay, Isabel M Costantino, George P McCabe, Matthew P Frosch, Julia M George, Erwan Bezard, Jean-Christophe Rochet
Neuropathological and genetic findings suggest that the presynaptic protein α-synuclein (aSyn) is involved in the pathogenesis of synucleinopathy disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. Evidence suggests that the self-assembly of aSyn conformers bound to phospholipid membranes in an aggregation-prone state plays a key role in aSyn neurotoxicity. Accordingly, we hypothesized that protein binding partners of lipid-associated aSyn could inhibit the formation of toxic aSyn oligomers at membrane surfaces...
January 10, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28057080/combination-of-alpha-synuclein-immunotherapy-with-anti-inflammatory-treatment-in-a-transgenic-mouse-model-of-multiple-system-atrophy
#6
Elvira Valera, Brian Spencer, Jerel A Fields, Ivy Trinh, Anthony Adame, Michael Mante, Edward Rockenstein, Paula Desplats, Eliezer Masliah
Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by the pathological accumulation of alpha-synuclein (α-syn) in oligodendrocytes. Therapeutic efforts to stop or delay the progression of MSA have yielded suboptimal results in clinical trials, and there are no efficient treatments currently available for MSA patients. We hypothesize that combining therapies targeting different aspects of the disease may lead to better clinical outcomes. To test this hypothesis, we combined the use of a single-chain antibody targeting α-syn modified for improved central nervous system penetration (CD5-D5) with an unconventional anti-inflammatory treatment (lenalidomide) in the myelin basic protein (MBP)-α-syn transgenic mouse model of MSA...
January 5, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28057070/distinct-pattern-of-enteric-phospho-alpha-synuclein-aggregates-and-gene-expression-profiles-in-patients-with-parkinson-s-disease
#7
Martina Barrenschee, Dimitri Zorenkov, Martina Böttner, Christina Lange, François Cossais, Amelie Bernadette Scharf, Günther Deuschl, Susanne A Schneider, Mark Ellrichmann, Annette Fritscher-Ravens, Thilo Wedel
Phosphorylated alpha-synuclein (p-α-syn) containing Lewy bodies (LBs) and Lewy neurites (LNs) are neuropathological hallmarks of Parkinson's disease (PD) in the central nervous system (CNS). Since they have been also demonstrated in the enteric nervous system (ENS) of PD patients, the aim of the study was to analyze enteric p-α-syn positive aggregates and intestinal gene expression. Submucosal rectal biopsies were obtained from patients with PD and controls and processed for dual-label-immunohistochemistry for p-α-syn and PGP 9...
January 5, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27955702/%C3%AE-amyloid-triggers-aberrant-over-scaling-of-homeostatic-synaptic-plasticity
#8
James Gilbert, Shu Shu, Xin Yang, Youming Lu, Ling-Qiang Zhu, Heng-Ye Man
The over-production of β-amyloid (Aβ) has been strongly correlated to neuronal dysfunction and altered synaptic plasticity in Alzheimer's disease (AD). Accordingly, it has been proposed that disrupted synaptic transmission and neuronal network instability underlie memory failure that is evident in the early phases of AD. Homeostatic synaptic plasticity (HSP) serves to restrain neuronal activity within a physiological range. Therefore a disruption of this mechanism may lead to destabilization in synaptic and neural circuit function...
December 13, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27955679/post-mortem-histopathology-underlying-%C3%AE-amyloid-pet-imaging-following-flutemetamol-f-18-injection
#9
Milos D Ikonomovic, Chris J Buckley, Kerstin Heurling, Paul Sherwin, Paul A Jones, Michelle Zanette, Chester A Mathis, William E Klunk, Aruna Chakrabarty, James Ironside, Azzam Ismail, Colin Smith, Dietmar R Thal, Thomas G Beach, Gill Farrar, Adrian P L Smith
In vivo imaging of fibrillar β-amyloid deposits may assist clinical diagnosis of Alzheimer's disease (AD), aid treatment selection for patients, assist clinical trials of therapeutic drugs through subject selection, and be used as an outcome measure. A recent phase III trial of [(18)F]flutemetamol positron emission tomography (PET) imaging in 106 end-of-life subjects demonstrated the ability to identify fibrillar β-amyloid by comparing in vivo PET to post-mortem histopathology. Post-mortem analyses demonstrated a broad and continuous spectrum of β-amyloid pathology in AD and other dementing and non-dementing disease groups...
December 12, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27938414/the-effects-of-the-novel-a53e-alpha-synuclein-mutation-on-its-oligomerization-and-aggregation
#10
Diana F Lázaro, Mariana Castro Dias, Anita Carija, Susanna Navarro, Carolina Silva Madaleno, Sandra Tenreiro, Salvador Ventura, Tiago F Outeiro
α-synuclein (aSyn) is associated with both sporadic and familial forms of Parkinson's disease (PD), the second most common neurodegenerative disorder after Alzheimer's disease. In particular, multiplications and point mutations in the gene encoding for aSyn cause familial forms of PD. Moreover, the accumulation of aSyn in Lewy Bodies and Lewy neurites in disorders such as PD, dementia with Lewy bodies, or multiple system atrophy, suggests aSyn misfolding and aggregation plays an important role in these disorders, collectively known as synucleinopathies...
December 9, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27931265/increased-caspase-6-activity-in-the-human-anterior-olfactory-nuclei-of-the-olfactory-bulb-is-associated-with-cognitive-impairment
#11
Benedicte Foveau, Steffen Albrecht, David A Bennett, José A Correa, Andrea C LeBlanc
Abnormally elevated hippocampal Caspase-6 (Casp6) activity is intimately associated with age-related cognitive impairment in humans and in mice. In humans, these high levels of Casp6 activity are initially localized in the entorhinal cortex, the area of the brain first affected by the formation of neurofibrillary tangles, according to Braak staging. The reason for the high vulnerability of entorhinal cortex neurons to neurofibrillary tangle pathology and Casp6 activity is unknown. Casp6 activity is involved in axonal degeneration, therefore, one possibility to explain increased vulnerability of the entorhinal cortex neurons would be that the afferent neurons of the olfactory bulb, some of which project their axons to the entorhinal cortex, are equally degenerating...
December 8, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27908295/dopamine-2-receptor-extracellular-n-terminus-regulates-receptor-surface-availability-and-is-the-target-of-human-pathogenic-antibodies-from-children-with-movement-and-psychiatric-disorders
#12
Nese Sinmaz, Fiona Tea, Deepti Pilli, Alicia Zou, Mazen Amatoury, Tina Nguyen, Vera Merheb, Sudarshini Ramanathan, Sandra T Cooper, Russell C Dale, Fabienne Brilot
Anti-Dopamine-2 receptor (D2R) antibodies have been recently identified in a subgroup of children with autoimmune movement and psychiatric disorders, however the epitope(s) and mechanism of pathogenicity remain unknown. Here we report a major biological role for D2R extracellular N-terminus as a regulator of receptor surface availability, and as a major epitope targeted and impaired in brain autoimmunity. In transfected human cells, purified anti-D2R antibody from patients specifically and significantly reduced human D2R surface levels...
December 1, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27894339/the-identification-of-human-pituitary-adenoma-initiating-cells
#13
Branavan Manoranjan, Sujeivan Mahendram, Saleh A Almenawer, Chitra Venugopal, Nicole McFarlane, Robin Hallett, Thusyanth Vijayakumar, Almunder Algird, Naresh K Murty, Doron D Sommer, John P Provias, Kesava Reddy, Sheila K Singh
Classified as benign central nervous system (CNS) tumors, pituitary adenomas account for 10% of diagnosed intracranial neoplasms. Although surgery is often curative, patients with invasive macroadenomas continue to experience significant morbidity and are prone to tumor recurrence. Given the identification of human brain tumor-initiating cells (TICs) that initiate and maintain tumor growth while promoting disease progression and relapse in multiple CNS tumors, we investigated whether TICs also drive the growth of human pituitary adenomas...
November 28, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27884214/neuronal-and-glial-changes-in-the-brain-resulting-from-explosive-blast-in-an-experimental-model
#14
James A Goodrich, Jung H Kim, Robert Situ, Wesley Taylor, Ted Westmoreland, Fu Du, Steven Parks, Geoffrey Ling, Jung Y Hwang, Amedeo Rapuano, Faris A Bandak, Nihal C de Lanerolle
Mild traumatic brain injury (mTBI) is the signature injury in warfighters exposed to explosive blasts. The pathology underlying mTBI is poorly understood, as this condition is rarely fatal and thus postmortem brains are difficult to obtain for neuropathological studies. Here we report on studies of an experimental model with a gyrencephalic brain that is exposed to single and multiple explosive blast pressure waves. To determine injuries to the brain resulting from the primary blast, experimental conditions were controlled to eliminate any secondary or tertiary injury from blasts...
November 24, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27884177/lrrk2-contributes-to-monocyte-dysregulation-in-parkinson-s-disease
#15
LETTER
Corinna Bliederhaeuser, Lisa Zondler, Veselin Grozdanov, Wolfgang P Ruf, David Brenner, Heather L Melrose, Peter Bauer, Albert C Ludolph, Frank Gillardon, Jan Kassubek, Jochen H Weishaupt, Karin M Danzer
No abstract text is available yet for this article.
November 24, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27863507/transgenic-mice-overexpressing-the-als-linked-protein-matrin-3-develop-a-profound-muscle-phenotype
#16
Christina Moloney, Sruti Rayaprolu, John Howard, Susan Fromholt, Hilda Brown, Matt Collins, Mariela Cabrera, Colin Duffy, Zoe Siemienski, Dave Miller, Maurice S Swanson, Lucia Notterpek, David R Borchelt, Jada Lewis
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of upper and lower motor neurons. Mutations in the gene encoding the nuclear matrix protein Matrin 3 have been found in familial cases of ALS, as well as autosomal dominant distal myopathy with vocal cord and pharyngeal weakness. We previously found that spinal cord and muscle, organs involved in either ALS or distal myopathy, have relatively lower levels of Matrin 3 compared to the brain and other peripheral organs in the murine system...
November 18, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27855725/review-of-ryr1-pathway-and-associated-pathomechanisms
#17
REVIEW
Jessica W Witherspoon, Katherine G Meilleur
Ryanodine receptor isoform-1 (RyR1) is a major calcium channel in skeletal muscle important for excitation-contraction coupling. Mutations in the RYR1 gene yield RyR1 protein dysfunction that manifests clinically as RYR1-related congenital myopathies (RYR1-RM) and/or malignant hyperthermia susceptibility (MHS). Individuals with RYR1-RM and/or MHS exhibit varying symptoms and severity. The symptoms impair quality of life and put patients at risk for early mortality, yet the cause of varying severity is not well understood...
November 17, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27842611/tau-pathology-in-aged-cynomolgus-monkeys-is-progressive-supranuclear-palsy-corticobasal-degeneration-but-not-alzheimer-disease-like-ultrastructural-mapping-of-tau-by-edx
#18
Toshiki Uchihara, Kentaro Endo, Hiromi Kondo, Sachi Okabayashi, Nobuhiro Shimozawa, Yasuhiro Yasutomi, Eijiro Adachi, Nobuyuki Kimura
Concomitant deposition of amyloid -beta protein (Aβ) and neuronal tau as neurofibrillary tangles in the human brain is a hallmark of Alzheimer disease (AD). Because these deposits increase during normal aging, it has been proposed that aging brains may also undergo AD-like changes. To investigate the neuropathological changes that occur in the aging primate brain, we examined 21 brains of cynomolgus monkeys (7-36 years old) for Aβ- and tau-positive lesions. We found, 1) extensive deposition of Aβ in brains of cynomolgus monkeys over 25 years of age, 2) selective deposition of 4-repeat tau as pretangles in neurons, and as coiled body-like structures in oligodendroglia-like cells and astrocytes, 3) preferential distribution of tau in the basal ganglia and neocortex rather than the hippocampus, and 4) age-associated increases in 30-34 kDa AT8- and RD4-positive tau fragments in sarkosyl-insoluble fractions...
November 14, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27842602/rubidium-and-potassium-levels-are-altered-in-alzheimer-s-disease-brain-and-blood-but-not-in-cerebrospinal-fluid
#19
Blaine R Roberts, James D Doecke, Alan Rembach, L Fernanda Yévenes, Christopher J Fowler, Catriona A McLean, Monica Lind, Irene Volitakis, Colin L Masters, Ashley I Bush, Dominic J Hare
Loss of intracellular compartmentalization of potassium is a biochemical feature of Alzheimer's disease indicating a loss of membrane integrity and mitochondrial dysfunction. We examined potassium and rubidium (a biological proxy for potassium) in brain tissue, blood fractions and cerebrospinal fluid from Alzheimer's disease and healthy control subjects to investigate the diagnostic potential of these two metal ions. We found that both potassium and rubidium levels were significantly decreased across all intracellular compartments in the Alzheimer's disease brain...
November 14, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27842578/an-autopsy-confirmed-case-of-progressive-supranuclear-palsy-with-predominant-postural-instability
#20
Carolin Kurz, Georg Ebersbach, Gesine Respondek, Armin Giese, Thomas Arzberger, Günter Ulrich Höglinger
Postural instability and supranuclear gaze palsy represent the key symptoms of Richardson's syndrome, the most frequent clinical manifestation of progressive supranuclear palsy (PSP). However, a proportion of PSP patients never develops ocular motor symptoms, which prevents clinicians from establishing the diagnosis during lifetime according to current diagnostic criteria. We present one instructive autopsy-confirmed PSP case with prospective video-documented clinical course, showing striking temporal divergence of initially present postural instability and delayed development of ocular motor dysfunction...
November 14, 2016: Acta Neuropathologica Communications
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