Induction of Inflammatory Mediators and Microglial Activation in Mice Transgenic for Mutant Human P301S Tau Protein

Bellucci, Arianna; Westwood, Andrew J.; Ingram, Esther; Casamenti, Fiorella; Goedert, Michel; Spillantini, Maria Grazia

doi:10.1016/s0002-9440(10)63421-9

Cited by 191 publications

(152 citation statements)

References 54 publications

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“…By 5 months of age P301S‐htau mice showed activated microglial cells that were mostly amoeboid‐shaped and clustered (Supporting Information Fig. 1) (Bellucci et al, 2004). Similar microglial clustering is frequently found in early stages of MS white matter in the absence of demyelination, but associated with axonal injury identified as accumulation of APP and non‐phosphorylated neurofilament (Singh et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Ossola

Zhao

Compston

et al. 2015

Glia

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Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule‐associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau‐induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S‐htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2‐month‐old P301S‐htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL‐1β and TNFα. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S‐htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S‐htau axons to demyelination‐induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S‐htau mice compared with Wt mice‐derived OPCs. Because the OPCs from P301S‐htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice‐derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination. GLIA 2016;64:457–471

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Section: Discussionmentioning

confidence: 99%

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Ossola

Zhao

Compston

et al. 2015

Glia

Self Cite

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“…All procedures were performed in compliance with national and institutional guidelines (UK Animals Scientific Procedures Act 1986 and the University of Cambridge Animal Care Committees). For characterization of neuronal cell loss, female and male homozygous P301S tau mice were killed at the onset of symptoms (Allen et al, 2002;Bellucci et al, 2004;Delobel et al, 2008;Gasparini et al, 2009) between 4 and 6 months of age, along with age-matched C57BL/6 mice. The mice are only allowed to survive to 5-6 months of age because of increasing hindlimb disability and United Kingdom Home Office animal license regulations requiring humane killing.…”

Section: Methodsmentioning

confidence: 99%

“…This transgenic model has previously been shown to accumulate hyperphosphorylated tau in neurons within a number of CNS regions, including cerebral cortex, amygdala, brainstem, and spinal cord, along with a neuroinflammatory response (Allen et al, 2002;Bellucci et al, 2004;Delobel et al, 2008;Gasparini et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Cell-Mediated Neuroprotection in a Mouse Model of Human Tauopathy

Hampton¹,

Webber²,

Bilican³

et al. 2010

J. Neurosci.

109

106

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Tau protein in a hyperphosphorylated state makes up the intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease and cases of frontotemporal dementia. Mutations in Tau cause familial forms of frontotemporal dementia, establishing that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. Transgenic mice expressing human mutant tau in neurons exhibit the essential features of tauopathies, including neurodegeneration and abundant filaments composed of hyperphosphorylated tau. Here we show that a previously described mouse line transgenic for human P301S tau exhibits an age-related, layer-specific loss of superficial cortical neurons, similar to what has been observed in human frontotemporal dementias. We also show that focal neural precursor cell implantation, resulting in glial cell differentiation, leads to the sustained rescue of cortical neurons. Together with evidence indicating that astrocyte transplantation may be neuroprotective, our findings suggest a beneficial role for glial cell-based repair in neurodegenerative diseases.

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“…In AD and other types of neurodegenerative diseases (27), a major role is attributed to microglia activation, which generates a primary inflammatory state (28). Leukocyte invasion is a secondary phenomenon (29,30).…”

Section: Cns Inflammation and The Cholinergic System Of The Basal Formentioning

confidence: 99%

Cognitive deficit associated with cholinergic and nerve growth factor down-regulation in experimental allergic encephalomyelitis in rats

D’Intino

Paradisi

Fernández

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Clinical symptoms in multiple sclerosis include cognitive dysfunction. Difficulties in learning and remembering new information represent the most common cognitive deficit and are associated with a general and progressive brain pathology. Possible pathogenetic mechanisms for neuronal damage such as neuroprotective strategies are under active investigation also in experimental allergic encephalomyelitis, the most widely used experimental model for multiple sclerosis. In this paper we demonstrate that a selective deficit in learning and memory performance, as investigated by the Morris water maze test, is a consistent feature in rat encephalomyelitis, which correlates with a decline in choline acetyltransferase activity and nerve growth factor mRNA level in cerebral cortex, hippocampus, and basal forebrain. Treatment aimed to restore acetylcholine content through chronic administration of selective acetylcholinesterase inhibitors (rivastigmine and donepezil) restores cognitive performance, choline acetyltransferase activity, and nerve growth factor mRNA expression.choline acetyltransferase ͉ multiple sclerosis ͉ learning and memory ͉ water maze ͉ acetylcholinesterase inhibitors

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Induction of Inflammatory Mediators and Microglial Activation in Mice Transgenic for Mutant Human P301S Tau Protein

Cited by 191 publications

References 54 publications

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Cell-Mediated Neuroprotection in a Mouse Model of Human Tauopathy

Cognitive deficit associated with cholinergic and nerve growth factor down-regulation in experimental allergic encephalomyelitis in rats

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