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Author(s): Marco Capogrosso [1, 2]; Tomislav Milekovic [1]; David Borton [1, 3]; Fabien Wagner [1]; Eduardo Martin Moraud [2]; Jean-Baptiste Mignardot [1]; Nicolas Buse [4]; Jerome Gandar [1]; Quentin Barraud [...]

Progressive supranuclear palsy (PSP) is a primary tauopathy affecting both neurons and glia and is responsible for both motor and cognitive symptoms. Recently, it has been suggested that PSP tauopathy may spread in the brain from cell to cell in a "prion-like" manner. However, direct experimental evidence of this phenomenon, and its consequences on brain functions, is still lacking in primates. In this study, we first derived sarkosyl-insoluble tau fractions from post-mortem brains of PSP patients. We also isolated the same fraction from age-matched control brains. Compared to control extracts, the in vitro characterization of PSP-tau fractions demonstrated a high seeding activity in P301S-tau expressing cells, displaying after incubation abnormally phosphorylated (AT8- and AT100-positivity), misfolded, filamentous (pFTAA positive), and sarkosyl-insoluble tau. We bilaterally injected two male rhesus macaques in the supranigral area with this fraction of PSP-tau proteopathic seeds, and two other macaques with the control fraction. The quantitative analysis of kinematic features revealed that PSP-tau injected macaques exhibited symptoms suggestive of parkinsonism as early as six months after injection, remaining present until sacrifice at 18 months. Object retrieval task showed the progressive appearance of a significant dysexecutive syndrome in PSP-tau injected macaques compared to controls. We found AT8-positive staining and 4R-tau inclusions only in PSP-tau injected macaques. Characteristic pathological hallmarks of PSP, including globose and neurofibrillary tangles, tufted astrocytes, and coiled bodies, were found close to the injection sites but also in connected brain regions that are known to be affected in PSP (striatum, pallidum, thalamus). Interestingly, while glial AT8-positive lesions were the most frequent near the injection site, we found mainly neuronal inclusions in the remote brain area, consistent with a neuronal transsynaptic spreading of the disease. Our results demonstrate that PSP patient-derived tau aggregates can induce motor and behavioral impairments in non-human primates related to the prion-like seeding and spreading of typical pathological PSP lesions. This pilot study pave the way for supporting PSP-tau injected macaque as a relevant animal model to accelerate drug development targeting this rare and fatal neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Abstract: Nanocrystalline Al-doped nickel ferrite powders have been synthesized by sol–gel auto-ignition method and the effect of non-magnetic aluminum content on the structural and magnetic properties has been studied. The X-ray diffraction (XRD) revealed that the powders obtained are single phase with inverse spinel structure. The calculated grain sizes from XRD data have been verified using transmission electron microscopy (TEM). TEM photographs show that the powders consist of nanometer-sized grains. It was observed that the characteristic grain size decreases from 29 to 6nm as the non-magnetic Al content increases, which was attributed to the influence of non-magnetic Al concentration on the grain size. Magnetic hysteresis loops were measured at room temperature with a maximum applied magnetic field of ≈1T. As aluminum content increases, the measured magnetic hysteresis curves become more and more narrow and the saturation magnetization and remanent magnetization both decreased. The reduction of magnetization compared to bulk is a consequence of spin non-collinearity. Further reduction of magnetization with increase of aluminum content is caused by non-magnetic Al3+ ions and weakened interaction between sublattices. This, as well as the decrease in hysteresis was understood in terms of the decrease in particle size. [Copyright &y& Elsevier]

Progressive supranuclear palsy is a primary tauopathy affecting both neurons and glia and is responsible for both motor and cognitive symptoms. Recently, it has been suggested that progressive supranuclear palsy tauopathy may spread in the brain from cell to cell in a 'prion-like' manner. However, direct experimental evidence of this phenomenon, and its consequences on brain functions, is still lacking in primates. In this study, we first derived sarkosyl-insoluble tau fractions from post-mortem brains of patients with progressive supranuclear palsy. We also isolated the same fraction from age-matched control brains. Compared to control extracts, the in vitro characterization of progressive supranuclear palsy-tau fractions demonstrated a high seeding activity in P301S-tau expressing cells, displaying after incubation abnormally phosphorylated (AT8- and AT100-positivity), misfolded, filamentous (pentameric formyl thiophene acetic acid positive) and sarkosyl-insoluble tau. We bilaterally injected two male rhesus macaques in the supranigral area with this fraction of progressive supranuclear palsy-tau proteopathic seeds, and two other macaques with the control fraction. The quantitative analysis of kinematic features revealed that progressive supranuclear palsy-tau injected macaques exhibited symptoms suggestive of parkinsonism as early as 6 months after injection, remaining present until euthanasia at 18 months. An object retrieval task showed the progressive appearance of a significant dysexecutive syndrome in progressive supranuclear palsy-tau injected macaques compared to controls. We found AT8-positive staining and 4R-tau inclusions only in progressive supranuclear palsy-tau injected macaques. Characteristic pathological hallmarks of progressive supranuclear palsy, including globose and neurofibrillary tangles, tufted astrocytes and coiled bodies, were found close to the injection sites but also in connected brain regions that are known to be affected in progressive supranuclear palsy (striatum, pallidum, thalamus). Interestingly, while glial AT8-positive lesions were the most frequent near the injection site, we found mainly neuronal inclusions in the remote brain area, consistent with a neuronal transsynaptic spreading of the disease. Our results demonstrate that progressive supranuclear palsy patient-derived tau aggregates can induce motor and behavioural impairments in non-human primates related to the prion-like seeding and spreading of typical pathological progressive supranuclear palsy lesions. This pilot study paves the way for supporting progressive supranuclear palsy-tau injected macaque as a relevant animal model to accelerate drug development targeting this rare and fatal neurodegenerative disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Parkinson's disease motor symptoms are treated with levodopa, but long-term treatment leads to disabling dyskinesia. Altered synaptic transmission and maladaptive plasticity of corticostriatal glutamatergic projections play a critical role in the pathophysiology of dyskinesia. Because the noble gas xenon inhibits excitatory glutamatergic signaling, primarily through allosteric antagonism of the N-methyl-d-aspartate receptors, we aimed to test its putative antidyskinetic capabilities. We first studied the direct effect of xenon gas exposure on corticostriatal plasticity in a murine model of levodopa-induced dyskinesia We then studied the impact of xenon inhalation on behavioral dyskinetic manifestations in the gold-standard rat and primate models of PD and levodopa-induced dyskinesia. Last, we studied the effect of xenon inhalation on axial gait and posture deficits in a primate model of PD with levodopa-induced dyskinesia. This study shows that xenon gas exposure (1) normalized synaptic transmission and reversed maladaptive plasticity of corticostriatal glutamatergic projections associated with levodopa-induced dyskinesia, (2) ameliorated dyskinesia in rat and nonhuman primate models of PD and dyskinesia, and (3) improved gait performance in a nonhuman primate model of PD. These results pave the way for clinical testing of this unconventional but safe approach. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)