Sialoadhesin promotes neuroinflammation‐related disease progression in two mouse models of <scp>CLN</scp> disease

Groh, Janos; Ribechini, Eliana; Stadler, David; Schilling, Tim; Lutz, Manfred B.; Martini, Rudolf

doi:10.1002/glia.22962

Cited by 47 publications

(72 citation statements)

References 55 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This led to a mild change in the composition of CD8+ T‐cells upon treatment: while in PLPmut mice 12.19% (±3.15%) of the CD8+ T‐cells were CD8+ CD122+ PD‐1+ regulatory T‐cells, this percentage was nonsignificantly increased to 20.04% (±11.55%; p = .36) after PLX3397 treatment. This change is a likely consequence of reduced numbers of Sn+ microglial cells which have previously been identified to control CD8+ CD122+ PD‐1+ regulatory T‐cells in another disease model (Groh, Ribechini, et al, ).…”

Section: Resultsmentioning

confidence: 86%

“…Mice were subjected to OCT imaging with a commercially available device (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany) and additional lenses as previously described (Groh et al, ; Groh, Friedman, et al, ; Groh, Stadler, Buttmann, & Martini, ). Mice were measured at different ages for longitudinal analysis and the thickness of the innermost retinal composite layer comprising nerve fiber layer (NFL), GCL, and inner plexiform layer (IPL) were measured in high‐resolution peripapillary circle scans (at least 10 measurements per scan) by an investigator unaware of the genotype of the mice.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Groh

Klein

Berve

et al. 2018

Glia

Self Cite

View full text Add to dashboard Cite

Genetically caused neurological disorders of the central nervous system (CNS) usually result in poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with disease‐amplifying neuroinflammation, a feature shared by progressive forms of multiple sclerosis (PMS), another poorly treatable disorder of the CNS. We have previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients fulfilling clinical criteria for multiple sclerosis (MS). These mutations cause a loss of function of the gene product resulting in a histopathological and clinical phenotype common to both PMS and genetic CNS disorders, like hereditary spastic paraplegias. Importantly, neuroinflammation comprising adaptive immune reactions promotes disease progression in these PLP1 mutant models, opening the possibility to improve disease outcome of the respective disorders by targeting/modulating inflammation. We here show that PLX3397, a potent inhibitor of the CSF‐1R and targeting innate immune cells, attenuates neuroinflammation in our models by reducing numbers of resident microglia and attenuating T‐lymphocyte recruitment in the CNS. This leads to an amelioration of demyelination, axonopathic features and neuron loss in the retinotectal system, also reflected by reduced thinning of the inner retinal composite layer in longitudinal studies using noninvasive optical coherence tomography. Our findings identify microglia as important promoters of neuroinflammation‐related neural damage and CSF‐1R inhibition as a possible therapeutic strategy not only for PMS but also for inflammation‐related genetic diseases of the nervous system for which causal treatment options are presently lacking.

show abstract

Section: Resultsmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Groh

Klein

Berve

et al. 2018

Glia

Self Cite

View full text Add to dashboard Cite

show abstract

“…Despite the progress in molecular genetics of the respective disorders, there is presently no cure available to mitigate the severe clinical burden. Since degenerative changes in the retina are diagnostically easily accessible for modern ophthalmologic imaging techniques, like optical coherence tomography, the retina can be viewed as surrogate tissue for these disorders (Bozorg, Ramirez-Montealegre, Chung, & Pearce, 2009;Groh et al, 2013Groh et al, , 2016bGroh, Stadler, Buttmann, & Martini, 2014;Haltia, 2006;Haltia & Goebel, 2013;Weleber et al, 2004). Murine models of both forms have been generated by disrupting the respective genes or introducing the most common human mutation using a "knock-in" approach and mimic the deficits observed in patients (Cotman et al, 2002;Gupta et al, 2001;Mitchison et al, 1999).…”

Section: Neuronal Ceroid Lipofuscinosesmentioning

confidence: 99%

“…Proof-of-principle crossbreeding and bone marrow transplantation approaches have unequivocally demonstrated that neuroinflammation comprising CD81 effector T-lymphocytes amplifies axonal perturbation, neurodegeneration, and clinical features in Ppt1 -/mice (Groh et al, 2013). Moreover, in addition to a pathogenic role of CD81 effector T-lymphocytes, activated microglia/macrophages expressing the proinflammatory cell adhesion molecule Sialoadhesin (Sn) were shown to amplify neural damage and clinical disease in the CLN1 and CLN3 disease models by crossbreeding approaches (Groh et al, 2016b). Moreover, in addition to a pathogenic role of CD81 effector T-lymphocytes, activated microglia/macrophages expressing the proinflammatory cell adhesion molecule Sialoadhesin (Sn) were shown to amplify neural damage and clinical disease in the CLN1 and CLN3 disease models by crossbreeding approaches (Groh et al, 2016b).…”

Section: Neuronal Ceroid Lipofuscinosesmentioning

confidence: 99%

“…Moreover, in addition to a pathogenic role of CD81 effector T-lymphocytes, activated microglia/macrophages expressing the proinflammatory cell adhesion molecule Sialoadhesin (Sn) were shown to amplify neural damage and clinical disease in the CLN1 and CLN3 disease models by crossbreeding approaches (Groh et al, 2016b). Additional microglia/macrophagerelated mechanisms are likely to contribute to the amplification of neural damage, as an increased expression of proinflammatory neurotoxic cytokines and oxidative damage have been reported in the mouse models (Benedict, Sommers, & Pearce, 2007;Groh et al, 2016b;Wei et al, 2008;Xiong & Kielian, 2013). Interestingly, one mechanism how Sn expression on microglia/macrophages contributes to disease progression is the suppression of CD8 1 CD1221 regulatory T-cells.…”

Section: Neuronal Ceroid Lipofuscinosesmentioning

confidence: 99%

See 1 more Smart Citation

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

Groh

Martini

2017

Glia

Self Cite

View full text Add to dashboard Cite

Genetically caused neurological disorders of the central nervous system (CNS) are usually orphan diseases with poor or even fatal clinical outcome and few or no treatments that will improve longevity or at least quality of life. Neuroinflammation is common to many of these disorders, despite the fact that a plethora of distinct mutations and molecular changes underlie the disorders. In this article, data from corresponding animal models are analyzed to define the roles of innate and adaptive inflammation as modifiers and amplifiers of disease. We describe both common and distinct patterns of neuroinflammation in genetically mediated CNS disorders and discuss the contrasting mechanisms that lead to adverse versus neuroprotective effects. Moreover, we identify the juxtaparanode as a neuroanatomical compartment commonly associated with inflammatory cells and ongoing axonopathic changes, in models of diverse diseases. The identification of key immunological effector pathways that amplify neuropathic features should lead to realistic possibilities for translatable therapeutic interventions using existing immunomodulators. Moreover, evidence emerges that neuroinflammation is not only able to modify primary neural damage-related symptoms but also may lead to unexpected clinical outcomes such as neuropsychiatric syndromes.

show abstract

Characterization of neurological disease progression in a canine model of CLN5 neuronal ceroid lipofuscinosis

Meiman

Kick

Jensen

et al. 2022

Developmental Neurobiology

View full text Add to dashboard Cite

Golden Retriever dogs with a frameshift variant in CLN5 (c.934_935delAG) suffer from a progressive neurodegenerative disorder analogous to the CLN5 form of neuronal ceroid lipofuscinosis (NCL). Five littermate puppies homozygous for the deletion allele were identified prior to the onset of disease signs. Studies were performed to characterize the onset and progression of the disease in these dogs. Neurological signs that included restlessness, unwillingness to cooperate with the handlers, and proprioceptive deficits first became apparent at approximately 12 months of age. The neurological signs progressed over time and by 21 to 23 months of age included general proprioceptive ataxia, menace response deficits, aggressive behaviors, cerebellar ataxia, intention tremors, decreased visual tracking, seizures, cognitive decline, and impaired prehension. Due to the severity of these signs, the dogs were euthanized between 21 and 23 months of age. Magnetic resonance imaging revealed pronounced progressive global brain atrophy with a more than sevenfold increase in the volume of the ventricular system between 9.5 and 22.5 months of age. Accompanying this atrophy were pronounced accumulations of autofluorescent inclusions throughout the brain and spinal cord. Ultrastructurally, the contents of these inclusions were found to consist primarily of membrane-like aggregates. Inclusions with similar fluorescence properties were present in cardiac muscle. Similar to other forms of NCL, the affected dogs had low plasma carnitine concentrations, suggesting impaired carnitine biosynthesis. These data on disease progression will be useful in future studies using the canine model for therapeutic intervention studies.

show abstract

Sialoadhesin promotes neuroinflammation‐related disease progression in two mouse models of CLN disease

Cited by 47 publications

References 55 publications

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

Characterization of neurological disease progression in a canine model of CLN5 neuronal ceroid lipofuscinosis

Contact Info

Product

Resources

About