Tracy L. Hagemann, PhD – Slide of the Week

Tracy L. Hagemann, PhD - Slide of the Week

Title: Depletion of macrophage lineage cells in Alexander disease model mice increases GFAP, suggesting microglia may be protective.

Legend: Treatment of Alexander disease model (AxD) and wild-type (WT) mice with pexidartinib (PEX), a selective CSF1R inhibitor, from weaning to 3 months of age reduces the number of macrophage lineage cells compared to untreated controls (CON), as demonstrated by IBA1+ cell counts (A), and increases GFAP accumulation (B) in AxD model mice. Results from hippocampus shown, *p < 0.05, ***p < 0.001, ANOVA with Bonferroni’s post-tests, n.s. = not significant, FOV = field of view.

Citation: Boyd, M. M., S. J. Litscher, L. L. Seitz, A. Messing, T. L. Hagemann and L. S. Collier (2021). Pexidartinib treatment in Alexander disease model mice reduces macrophage numbers and increases glial fibrillary acidic protein levels, yet has minimal impact on other disease phenotypes. J Neuroinflammation 18(1): 67.

Abstract: Background – Alexander disease (AxD) is a rare neurodegenerative disorder that is caused by dominant mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament that is primarily expressed by astrocytes. In AxD, mutant GFAP in combination with increased GFAP expression result in astrocyte dysfunction and the accumulation of Rosenthal fibers. A neuroinflammatory environment consisting primarily of macrophage lineage cells has been observed in AxD patients and mouse models. Methods – To examine if macrophage lineage cells could serve as a therapeutic target in AxD, GFAP knock-in mutant AxD model mice were treated with a colony-stimulating factor 1 receptor (CSF1R) inhibitor, pexidartinib. The effects of pexidartinib treatment on disease phenotypes were assessed. Results – In AxD model mice, pexidartinib administration depleted macrophages in the CNS and caused elevation of GFAP transcript and protein levels with minimal impacts on other phenotypes including body weight, stress response activation, chemokine/cytokine expression, and T cell infiltration. Conclusions – Together, these results highlight the complicated role that macrophages can play in neurological diseases and do not support the use of pexidartinib as a therapy for AxD.

About the Lab: The Alexander Disease lab is focused on understanding developmental and pathological aspects of glial cell biology in the nervous system of the mouse, with a particular focus on astrocytes and their major intermediate filament protein, GFAP. Main strategies involve genetic manipulation of glial gene expression using transgenic techniques, and gene targeting in embryonic stem cells to generate mutant strains of mice. Current projects address a variety of topics, such as regulation of gene expression, and the role of GFAP mutations and accumulation in the pathogenesis of AxD. A major effort is devoted to devising novel therapeutic strategies for treatment of this disorder, and identifying biomarkers to permit monitoring severity or progression of the disease.

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