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Updated: Dec 5, 2025
An In Vitro Model for the Study of Cellular Pathophysiology in Globoid Cell Leukodystrophy
Published on: October 21, 2014
Microglial reduction of colony stimulating factor-1 receptor expression is sufficient to confer adult onset
Fabrizio Biundo1, Violeta Chitu1, Gabriel G L Shlager1
1Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
Abstract:
Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a dementia resulting from dominantly inherited CSF1R inactivating mutations. The Csf1r+/- mouse mimics ALSP symptoms and pathology. Csf1r is mainly expressed in microglia, but also in cortical layer V neurons that are gradually lost in Csf1r+/- mice with age. We therefore examined whether microglial or neuronal Csf1r loss caused neurodegeneration in Csf1r+/- mice. The behavioral deficits, pathologies and elevation of Csf2 expression contributing to disease, previously described in the Csf1r+/- ALSP mouse, were reproduced by microglial deletion (MCsf1rhet mice), but not by neural deletion. Furthermore, increased Csf2 expression by callosal astrocytes, oligodendrocytes, and microglia was observed in Csf1r+/- mice and, in MCsf1rhet mice, the densities of these three cell types were increased in supraventricular patches displaying activated microglia, an early site of disease pathology. These data confirm that ALSP is a primary microgliopathy and inform future therapeutic and experimental approaches.
Insights
Adult Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) is a dementia caused by CSF1R mutations. Microglial CSF1R loss, not neuronal loss, drives ALSP pathology in mice, confirming it as a primary microgliopathy.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Adult Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) is a rare dementia linked to CSF1R gene mutations.
- The Csf1r+/- mouse model recapitulates ALSP symptoms and pathology.
- CSF1R is expressed in both microglia and cortical neurons, raising questions about the cell type responsible for neurodegeneration.
Purpose of the Study:
- To determine whether microglial or neuronal Csf1r loss drives neurodegeneration in the ALSP mouse model.
- To investigate the role of Csf2 expression in ALSP pathogenesis.
Main Methods:
- Conditional microglial-specific deletion of Csf1r in mice (MCsf1rhet).
- Comparison of behavioral deficits and neuropathology between MCsf1rhet mice and Csf1r+/- mice.
- Analysis of Csf2 expression and glial cell densities in affected brain regions.
Main Results:
- Microglial deletion of Csf1r (MCsf1rhet) reproduced ALSP-like behavioral deficits and pathologies.
- Neuronal deletion of Csf1r did not cause ALSP-like symptoms.
- Increased Csf2 expression and glial cell densities were observed in affected brain areas of MCsf1rhet mice.
Conclusions:
- ALSP is confirmed as a primary microgliopathy, driven by Csf1r loss in microglia.
- These findings highlight the critical role of microglial CSF1R in maintaining brain health.
- The study provides insights for future therapeutic strategies targeting microglial dysfunction in ALSP.
