University of Oxford
Clinical Neurosciences

Author Of 1 Presentation

Pathogenesis – Role of Glia Poster Presentation

P0942 - Astrocyte Topography Throughout the Multiple Sclerosis Motor Cortex and its Relationships with Genotype and Pathological Outcome  (ID 87)

Speakers
Presentation Number
P0942
Presentation Topic
Pathogenesis – Role of Glia

Abstract

Background

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, leading to substantial and irreversible disability. HLA-DRB1*15 gene confers the greatest MS risk, with MS 15+ individuals displaying more severe inflammation and demyelination. Yet, the mechanisms underlying this specific genotype remain elusive. Astrocytes are likely early and active contributors of MS pathogenesis due to their integral role in blood-brain barrier maintenance, neurotrophic support, and immune regulation. Dysfunctional astrocytes can lead to cytotoxicity, engaging with activated microglia to create a toxic cycle of inflammation and neurodegeneration. However, astrocyte topography in the MS motor cortex and its relationships with genotype and pathological outcome have been overlooked and is therefore, the focus of this study.

Objectives

To characterize astrocyte pathology in the post-mortem MS motor cortex by assessing the morphological phenotypes of astrocyte populations in MS, evaluating the influence of HLA-DRB1*15 status, and relating pathological outcomes to astroglial phenotypes.

Methods

A cohort of pathological confirmed MS (n=47; HLA-DRB1*15-, n=26; HLA-DRB1*15+, n=21), and non-neurological control cases (n=7) was used. Adjacent formalin-fixed, paraffin-embedded motor cortical sections were immunolabelled for astrocytes (ALDH1L1, GFAP). Pixel density (pixel/mm2) was used to asses astrocyte expression in pre-defined trajectories spaced at systematic intervals of the motor cortex and correlated to genotype status, neuronal (NeuN), and microglia/macrophage densities (IBA1; CD68).

Results

ALDH1L1 expression was greatest in the grey matter (p<0.0001), whereas GFAP expression was greatest in the white matter (p<0.0001). GFAP was influenced by HLA-DRB1*15, especially in cases equal to or younger than the median age of 62-years old, with 15+ individuals expressing greater GFAP expression than their 15- counterparts (p=0.014). Although CD68 correlation with GFAP was lost in MS (r=-0.107, p=0.473), ALDH1L1 positively correlated with CD68 in HLA-DRB1*15-cases (r=-.549, p=0.004), especially in cases older than 62-years old (r=0.936, p=0.006).

Conclusions

The striking differences between ALDH1L1 and GFAP, suggest that there are distinct astrocyte populations present in the MS motor cortex, which may play a crucial role in understanding MS heterogeneity. HLA-DRB1*15 genotype appears to influences astrocyte reactivity and likely mitigates components of the astrocyte-microglia/macrophage relationship. These findings suggest a significant impact of genetic background on MS astrocyte populations, which when disrupted from appropriate expression, may contribute to cytotoxic inflammation and subsequent disability.

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Presenter Of 1 Presentation

Pathogenesis – Role of Glia Poster Presentation

P0942 - Astrocyte Topography Throughout the Multiple Sclerosis Motor Cortex and its Relationships with Genotype and Pathological Outcome  (ID 87)

Speakers
Presentation Number
P0942
Presentation Topic
Pathogenesis – Role of Glia

Abstract

Background

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, leading to substantial and irreversible disability. HLA-DRB1*15 gene confers the greatest MS risk, with MS 15+ individuals displaying more severe inflammation and demyelination. Yet, the mechanisms underlying this specific genotype remain elusive. Astrocytes are likely early and active contributors of MS pathogenesis due to their integral role in blood-brain barrier maintenance, neurotrophic support, and immune regulation. Dysfunctional astrocytes can lead to cytotoxicity, engaging with activated microglia to create a toxic cycle of inflammation and neurodegeneration. However, astrocyte topography in the MS motor cortex and its relationships with genotype and pathological outcome have been overlooked and is therefore, the focus of this study.

Objectives

To characterize astrocyte pathology in the post-mortem MS motor cortex by assessing the morphological phenotypes of astrocyte populations in MS, evaluating the influence of HLA-DRB1*15 status, and relating pathological outcomes to astroglial phenotypes.

Methods

A cohort of pathological confirmed MS (n=47; HLA-DRB1*15-, n=26; HLA-DRB1*15+, n=21), and non-neurological control cases (n=7) was used. Adjacent formalin-fixed, paraffin-embedded motor cortical sections were immunolabelled for astrocytes (ALDH1L1, GFAP). Pixel density (pixel/mm2) was used to asses astrocyte expression in pre-defined trajectories spaced at systematic intervals of the motor cortex and correlated to genotype status, neuronal (NeuN), and microglia/macrophage densities (IBA1; CD68).

Results

ALDH1L1 expression was greatest in the grey matter (p<0.0001), whereas GFAP expression was greatest in the white matter (p<0.0001). GFAP was influenced by HLA-DRB1*15, especially in cases equal to or younger than the median age of 62-years old, with 15+ individuals expressing greater GFAP expression than their 15- counterparts (p=0.014). Although CD68 correlation with GFAP was lost in MS (r=-0.107, p=0.473), ALDH1L1 positively correlated with CD68 in HLA-DRB1*15-cases (r=-.549, p=0.004), especially in cases older than 62-years old (r=0.936, p=0.006).

Conclusions

The striking differences between ALDH1L1 and GFAP, suggest that there are distinct astrocyte populations present in the MS motor cortex, which may play a crucial role in understanding MS heterogeneity. HLA-DRB1*15 genotype appears to influences astrocyte reactivity and likely mitigates components of the astrocyte-microglia/macrophage relationship. These findings suggest a significant impact of genetic background on MS astrocyte populations, which when disrupted from appropriate expression, may contribute to cytotoxic inflammation and subsequent disability.

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