Tauopathy-like Abnormalities and Neurologic Deficits in Mice Immunized With Neuronal Tau Protein

Rosenmann, Hanna; Grigoriadis, Nikolaos; Karussis, Dimitrios; Boimel, Moran; Touloumi, Olga; Ovadia, Haim; Abramsky, Oded

doi:10.1001/archneur.63.10.1459

Cited by 168 publications

(133 citation statements)

References 25 publications

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“…Indeed, T cell responses against neuronal antigens have been demonstrated in MS patients and EAE- affected animals [8][9][10], and T cell-mediated EAE symptoms can be induced by immunization with neuronal antigens [11,13,14]. Despite this, we did not detect T cell proliferation against NF-L in CLN from EAE mice immunized with MOG or MOG [8][9][10][11][12][13][14][15][16][17][18][19][20][21] . The lack of T cell proliferation we consistently found might be due to the absence of intermolecular spreading or to the fact that the draining antigens may act immunosuppressively on proliferation within the draining lymph nodes.…”

Section: Discussioncontrasting

confidence: 65%

“…EAE was induced by immunization with spinal cord homogenate or myelin oligodendrocyte glycoprotein (MOG) [8][9][10][11][12][13][14][15][16][17][18][19][20][21] in CFA as described [27,28]. Deep and superficial CLN were also isolated from CCR7-deficient (n=4) and wild-type mice (n=4) [29] with chronic EAE, obtained from stock bred at the animal facility of the Max Delbrück Center for Molecular Medicine (Berlin, Germany).…”

Section: Eae Tissuesmentioning

confidence: 99%

“…A single cell suspension was obtained by passing the lymph nodes through a 70-μm gauze. Lymph node cells, 2×10 5 , were seeded into 96-well round-bottomed plates (Nunc) and stimulated with the indicated concentrations of MOG [8][9][10][11][12][13][14][15][16][17][18][19][20][21] , MOG (both from Advanced Biotechnology Center, Imperial College London), recombinant mouse NF-L (rmNF-L) [40], or ovalbumin (Worthington). After 4 days, T cell proliferation was determined by incorporation of [ 3 H]-thymidine for 18 h (Amersham Biosciences) as described [30].…”

Section: T Cell Proliferation Assaymentioning

confidence: 99%

“…Two experiments were using C57BL/6 mice in which EAE was induced by injection with MOG 35-55 (n=5-10 per experiment). One additional experiment was using Biozzi ABH mice (n=10) in which EAE was induced by injection with MOG [8][9][10][11][12][13][14][15][16][17][18][19][20][21] . Figure 5 shows a representative experiment, in which we observed dose-dependent T cell proliferation against the immunizing peptide MOG No proliferation against the irrelevant control antigen OVA was seen.…”

Section: Neuronal Antigen-containing Cells Have An Apc Phenotypementioning

confidence: 99%

“…In addition, T cells from MS patients proliferate in response to the neuronal antigens synapsin and neuron-specific enolase (NSE) [8,9]. In mice, T-cell-mediated autoimmunity against neuronal antigens leads to central nervous system (CNS) inflammation and experimental autoimmune encephalomyelitis (EAE) symptoms [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

et al. 2008

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Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in J Mol Med (2009) human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked.

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Section: Discussioncontrasting

confidence: 65%

Section: Eae Tissuesmentioning

confidence: 99%

Section: T Cell Proliferation Assaymentioning

confidence: 99%

Section: Neuronal Antigen-containing Cells Have An Apc Phenotypementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

et al. 2008

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Acute Disseminated Encephalomyelitis: Idiopathic, Post‐infectious, and Post‐vaccination

Karussis¹,

Petrou²

2015

Vaccines and Autoimmunity

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Passive immunotherapy of tauopathy targeting pSer413‐tau: a pilot study in mice

Umeda

Eguchi

Kunori

et al. 2015

Ann Clin Transl Neurol

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ObjectiveCellular inclusions of hyperphosphorylated tau are a hallmark of tauopathies, which are neurodegenerative disorders that include Alzheimer's disease (AD). Active and passive immunization against hyperphosphorylated tau has been shown to attenuate phenotypes in model mice. We developed new monoclonal antibodies to hyperphosphorylated tau and sought high therapeutic efficacy for future clinical use.MethodsUsing more than 20 antibodies, we investigated which sites on tau are phosphorylated early and highly in the tauopathy mouse models tau609 and tau784. These mice display tau hyperphosphorylation, synapse loss, memory impairment at 6 months, and tangle formation and neuronal loss at 15 months. We generated mouse monoclonal antibodies to selected epitopes and examined their effects on memory and tau pathology in aged tau609 and tau784 mice by the Morris water maze and by histological and biochemical analyses.ResultsImmunohistochemical screening revealed that pSer413 is expressed early and highly. Monoclonal antibodies to pSer413 and to pSer396 (control) were generated. These antibodies specifically recognized pathological tau in AD brains but not normal tau in control brains according to Western blots. Representative anti-pSer413 and anti-pSer396 antibodies were injected intraperitoneally into 10–11- or 14-month-old mice once a week at 0.1 or 1 mg/shot 5 times. The anti-pSer413 antibody significantly improved memory, whereas the anti-pSer396 antibodies showed less effect. The cognitive improvement paralleled a reduction in the levels of tau hyperphosphorylation, tau oligomer accumulation, synapse loss, tangle formation, and neuronal loss.InterpretationThese results indicate that pSer413 is a promising target in the treatment of tauopathy.

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Tauopathy-like Abnormalities and Neurologic Deficits in Mice Immunized With Neuronal Tau Protein

Cited by 168 publications

References 25 publications

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Acute Disseminated Encephalomyelitis: Idiopathic, Post‐infectious, and Post‐vaccination

Passive immunotherapy of tauopathy targeting pSer413‐tau: a pilot study in mice

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