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Individual Cytokines Modulate the Neurological Symptoms of ATM Deficiency in a Region Specific Manner(1,2,3).

Hui CW, Herrup K - eNeuro (2015)

Bottom Line: Nongenetic factors, including modulations of the immune status of the animal, have also recently been found to play a role in the disease phenotype.Tracking these changes reveals an important though not exclusive role for the MAP kinase pathway.This implies that management of the immune status of A-T patients might have significant clinical benefit.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Life Science, The Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong.

ABSTRACT
Ataxia-telangiectasia (A-T) is a multisystemic neurodegenerative disease of childhood caused by the absence of functional ATM (A-T mutated) protein. The cerebellar cortex has the most obvious neuropathology, yet cells in other brain regions are also abnormal. A-T mouse models have been produced that replicate much, though not all, of the complex A-T phenotype. Nongenetic factors, including modulations of the immune status of the animal, have also recently been found to play a role in the disease phenotype. Here we report that these modulations show both cytokine and brain region specificity. The CNS changes induced by broad-spectrum immune challenges, such as lipopolysaccharide (LPS) injections are a complex mixture of neuroprotective (TNFα) and neurodegenerative (IL1β) cytokine responses that change over time. For example, LPS first induces a protective response in A-T neurons through activation of tissue repair genes through infiltration of monocytes with M2 phenotype, followed over time by a set of more degenerative responses. Additional phenotypic complexity arises because the neuronal response to an immune challenge is regionally variable; cerebellum and cortex differ in important ways in their patterns of cellular and biochemical changes. Tracking these changes reveals an important though not exclusive role for the MAP kinase pathway. Our findings suggest brain responses to cytokine challenges are temporally and regionally specific and that both features are altered by the absence of ATM. This implies that management of the immune status of A-T patients might have significant clinical benefit.

No MeSH data available.


Related in: MedlinePlus

Persistent effects of an immune challenge in Atm−/−, but not wild-type mice. In both wild-type and Atm−/− cerebellum, microglia (A–D) and astrocytes (E–H) had returned to resting morphologies after a 1 month recovery. Despite this, calbindin staining revealed that in LPS challenged Atm−/−mice (J) the Purkinje cells remained dystrophic compared with Purkinje cells in untreated Atm−/−animals (I). In cortex, Iba-1 staining revealed the persistence of activated microglia in LPS-treated mutant (Atm−/−) animals but not in wild-type (K–N). Astrocyte morphologies returned to resting states in all animal groups (O–R). GC, Granule cell layer; ML, molecular layer. Scale bar, 50 µm. n = 3 for each group.
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Figure 8: Persistent effects of an immune challenge in Atm−/−, but not wild-type mice. In both wild-type and Atm−/− cerebellum, microglia (A–D) and astrocytes (E–H) had returned to resting morphologies after a 1 month recovery. Despite this, calbindin staining revealed that in LPS challenged Atm−/−mice (J) the Purkinje cells remained dystrophic compared with Purkinje cells in untreated Atm−/−animals (I). In cortex, Iba-1 staining revealed the persistence of activated microglia in LPS-treated mutant (Atm−/−) animals but not in wild-type (K–N). Astrocyte morphologies returned to resting states in all animal groups (O–R). GC, Granule cell layer; ML, molecular layer. Scale bar, 50 µm. n = 3 for each group.

Mentions: Iba-1 and GFAP immunohistochemistry showed that astrocyte morphologies returned to normal not only in wild-type, but also in Atm−/−after the 1 month recovery (Fig. 8E–H,O–R). The microglial recovery was incomplete in the mutant, however. Whereas in Atm−/− cerebellum Iba1 cells returned to their resting state (Fig. 8H), in Atm−/−cortex, Iba1-positive cells with an activated morphology persisted even after the 1 month recovery period (Fig. 8N). In keeping with this incomplete recovery of the immune response cells, the neurons of the Atm−/−brain also showed lingering deficits one month after the LPS injections were stopped (Tables 1 and 2). Most prominent among these was the number of cyclin A-positive neurons; these remained significantly higher in LPS-treated Atm−/−mice (p < 0.01) compared with saline-injected mutants. The incomplete recovery of the mutants could also be seen in the appearance of the Atm−/−Purkinje cell dendritic morphology. Calbindin immunostaining showed continuing structural deficits even 1 month following the LPS challenge (Fig. 8J, compare with I, untreated Atm−/− cerebellum.


Individual Cytokines Modulate the Neurological Symptoms of ATM Deficiency in a Region Specific Manner(1,2,3).

Hui CW, Herrup K - eNeuro (2015)

Persistent effects of an immune challenge in Atm−/−, but not wild-type mice. In both wild-type and Atm−/− cerebellum, microglia (A–D) and astrocytes (E–H) had returned to resting morphologies after a 1 month recovery. Despite this, calbindin staining revealed that in LPS challenged Atm−/−mice (J) the Purkinje cells remained dystrophic compared with Purkinje cells in untreated Atm−/−animals (I). In cortex, Iba-1 staining revealed the persistence of activated microglia in LPS-treated mutant (Atm−/−) animals but not in wild-type (K–N). Astrocyte morphologies returned to resting states in all animal groups (O–R). GC, Granule cell layer; ML, molecular layer. Scale bar, 50 µm. n = 3 for each group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 8: Persistent effects of an immune challenge in Atm−/−, but not wild-type mice. In both wild-type and Atm−/− cerebellum, microglia (A–D) and astrocytes (E–H) had returned to resting morphologies after a 1 month recovery. Despite this, calbindin staining revealed that in LPS challenged Atm−/−mice (J) the Purkinje cells remained dystrophic compared with Purkinje cells in untreated Atm−/−animals (I). In cortex, Iba-1 staining revealed the persistence of activated microglia in LPS-treated mutant (Atm−/−) animals but not in wild-type (K–N). Astrocyte morphologies returned to resting states in all animal groups (O–R). GC, Granule cell layer; ML, molecular layer. Scale bar, 50 µm. n = 3 for each group.
Mentions: Iba-1 and GFAP immunohistochemistry showed that astrocyte morphologies returned to normal not only in wild-type, but also in Atm−/−after the 1 month recovery (Fig. 8E–H,O–R). The microglial recovery was incomplete in the mutant, however. Whereas in Atm−/− cerebellum Iba1 cells returned to their resting state (Fig. 8H), in Atm−/−cortex, Iba1-positive cells with an activated morphology persisted even after the 1 month recovery period (Fig. 8N). In keeping with this incomplete recovery of the immune response cells, the neurons of the Atm−/−brain also showed lingering deficits one month after the LPS injections were stopped (Tables 1 and 2). Most prominent among these was the number of cyclin A-positive neurons; these remained significantly higher in LPS-treated Atm−/−mice (p < 0.01) compared with saline-injected mutants. The incomplete recovery of the mutants could also be seen in the appearance of the Atm−/−Purkinje cell dendritic morphology. Calbindin immunostaining showed continuing structural deficits even 1 month following the LPS challenge (Fig. 8J, compare with I, untreated Atm−/− cerebellum.

Bottom Line: Nongenetic factors, including modulations of the immune status of the animal, have also recently been found to play a role in the disease phenotype.Tracking these changes reveals an important though not exclusive role for the MAP kinase pathway.This implies that management of the immune status of A-T patients might have significant clinical benefit.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Life Science, The Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong.

ABSTRACT
Ataxia-telangiectasia (A-T) is a multisystemic neurodegenerative disease of childhood caused by the absence of functional ATM (A-T mutated) protein. The cerebellar cortex has the most obvious neuropathology, yet cells in other brain regions are also abnormal. A-T mouse models have been produced that replicate much, though not all, of the complex A-T phenotype. Nongenetic factors, including modulations of the immune status of the animal, have also recently been found to play a role in the disease phenotype. Here we report that these modulations show both cytokine and brain region specificity. The CNS changes induced by broad-spectrum immune challenges, such as lipopolysaccharide (LPS) injections are a complex mixture of neuroprotective (TNFα) and neurodegenerative (IL1β) cytokine responses that change over time. For example, LPS first induces a protective response in A-T neurons through activation of tissue repair genes through infiltration of monocytes with M2 phenotype, followed over time by a set of more degenerative responses. Additional phenotypic complexity arises because the neuronal response to an immune challenge is regionally variable; cerebellum and cortex differ in important ways in their patterns of cellular and biochemical changes. Tracking these changes reveals an important though not exclusive role for the MAP kinase pathway. Our findings suggest brain responses to cytokine challenges are temporally and regionally specific and that both features are altered by the absence of ATM. This implies that management of the immune status of A-T patients might have significant clinical benefit.

No MeSH data available.


Related in: MedlinePlus