Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy

Nash, Kevin; Lee, Daniel; Hunt, Jerry B.; Morganti, Josh M.; Selenica, Maj Linda B.; Moran, P.; Reid, Patrick; Brownlow, Milene; Yang, Clement G.Y.; Savalia, Miloni; Gemma, Carmelina; Bickford, Paula C.; Gordon, Marcia N.; Morgan, David

doi:10.1016/j.neurobiolaging.2012.12.011

Cited by 92 publications

(98 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, a deficit in short term object recognition memory was also apparent by 4 months of age and was maintained out to 6 months of age. These behavioral deficits build on similar findings in the rTg4510 mice reported by other labs [22], [24], [28], [30], and may represent phenotypes useful for testing functional effects of anti-inflammatory agents. Indeed, reversal of hyperactivity has been shown recently to be a successful measure of functional rescue in rTg4510 mice [28], [50].…”

Section: Discussionsupporting

confidence: 85%

“…These behavioral deficits build on similar findings in the rTg4510 mice reported by other labs [22], [24], [28], [30], and may represent phenotypes useful for testing functional effects of anti-inflammatory agents. Indeed, reversal of hyperactivity has been shown recently to be a successful measure of functional rescue in rTg4510 mice [28], [50]. The underlying mechanisms of the various behavioral deficits remains unclear, though increased anxiety could be a factor contributing to the increased locomotor activity and stereotypy, and may also interfere with the animal’s ability to perform cognitive tasks.…”

Section: Discussionsupporting

confidence: 85%

See 1 more Smart Citation

Tau Overexpression Impacts a Neuroinflammation Gene Expression Network Perturbed in Alzheimer’s Disease

et al. 2014

View full text Add to dashboard Cite

Filamentous inclusions of the microtubule-associated protein, tau, define a variety of neurodegenerative diseases known as tauopathies, including Alzheimer’s disease (AD). To better understand the role of tau-mediated effects on pathophysiology and global central nervous system function, we extensively characterized gene expression, pathology and behavior of the rTg4510 mouse model, which overexpresses a mutant form of human tau that causes Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We found that the most predominantly altered gene expression pathways in rTg4510 mice were in inflammatory processes. These results closely matched the causal immune function and microglial gene-regulatory network recently identified in AD. We identified additional gene expression changes by laser microdissecting specific regions of the hippocampus, which highlighted alterations in neuronal network activity. Expression of inflammatory genes and markers of neuronal activity changed as a function of age in rTg4510 mice and coincided with behavioral deficits. Inflammatory changes were tau-dependent, as they were reversed by suppression of the tau transgene. Our results suggest that the alterations in microglial phenotypes that appear to contribute to the pathogenesis of Alzheimer’s disease may be driven by tau dysfunction, in addition to the direct effects of beta-amyloid.

show abstract

Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 85%

Tau Overexpression Impacts a Neuroinflammation Gene Expression Network Perturbed in Alzheimer’s Disease

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Previous studies using murine AD models have demonstrated that chemokine receptor systems such as CCR5 (36), CCR2 (37)(38)(39), and CX3CR1 (40)(41)(42)(43) can modulate the disease course by influencing microglial function, accumulation, and clustering (37,(40)(41)(42). In addition, a positive correlation between CXCL10 concentrations in the cerebrospinal fluid and cognitive impairment in AD patients has been demonstrated (44,45).…”

Section: Introductionmentioning

confidence: 97%

CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model

Krauthausen¹,

Kummer²,

Zimmermann³

et al. 2014

J. Clin. Invest.

114

View full text Add to dashboard Cite

“…Furthermore, the importance of chemokines has been demonstrated in other diseases that are characterized by myelin abnormalities and/or oligodendrocyte pathology, including amyotrophic lateral sclerosis (27), Alzheimer's disease (28), leukodystrophies (29), or schizophrenia (30).…”

mentioning

confidence: 99%

CXCL10 Triggers Early Microglial Activation in the Cuprizone Model

Clarner

Janssen

Nellessen

et al. 2015

The Journal of Immunology

113

View full text Add to dashboard Cite

A broad spectrum of diseases is characterized by myelin abnormalities and/or oligodendrocyte pathology. In most, if not all, of these diseases, early activation of microglia occurs. Our knowledge regarding the factors triggering early microglia activation is, however, incomplete. In this study, we used the cuprizone model to investigate the temporal and causal relationship of oligodendrocyte apoptosis and early microglia activation. Genome-wide gene expression studies revealed the induction of distinct chemokines, among them Cxcl10, Ccl2, and Ccl3 in cuprizone-mediated oligodendrocyte apoptosis. Early microglia activation was unchanged in CCL2- and CCL3-deficient knockouts, but was significantly reduced in CXCL10-deficient mice, resulting in an amelioration of cuprizone toxicity at later time points. Subsequent in vitro experiments revealed that recombinant CXCL10 induced migration and a proinflammatory phenotype in cultured microglia, without affecting their phagocytic activity or proliferation. In situ hybridization analyses suggest that Cxcl10 mRNA is mainly expressed by astrocytes, but also oligodendrocytes, in short-term cuprizone-exposed mice. Our results show that CXCL10 actively participates in the initiation of microglial activation. These findings have implications for the role of CXCL10 as an important mediator during the initiation of neuroinflammatory processes associated with oligodendrocyte pathology.

show abstract

Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy

Cited by 92 publications

References 48 publications

Tau Overexpression Impacts a Neuroinflammation Gene Expression Network Perturbed in Alzheimer’s Disease

Tau Overexpression Impacts a Neuroinflammation Gene Expression Network Perturbed in Alzheimer’s Disease

CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model

CXCL10 Triggers Early Microglial Activation in the Cuprizone Model

Contact Info

Product

Resources

About