Objective: We will characterize neuropathological alterations of astrocytes in different regions of the FXTAS brain.

Background: FXTAS is a progressive neurodegenerative disorder that occurs in some individuals with FMR1 premutation. The temporal, spatial, and cell-type specific patterns of neurodegeneration in the FXTAS brain remain incompletely characterized. While FXTAS inclusion bodies are present in both astrocytes and neurons, they are larger and occur at a higher rate in astrocytes.

Method: Postmortem striatal and cerebellar tissue from FXTAS patients (n=12) and matched controls (n=12) were sectioned at 16μm and stained for GFAP using enzymatic immunohistochemistry, and for GFAP and Cleaved Caspase-3 using immunofluorescence. 40x images were acquired from both grey and white matter of each brain region, and individual astrocytes were scored for reactive gliosis severity using an established Likert scale (I-IV).

Results: FXTAS cases showed severe reactive gliosis in both grey and white matter. A high proportion of astrocytes showed a severe reactive phenotype, marked by gemistocytic cell bodies, intense GFAP staining, and clear blebbing of astrocytic processes. We found a substantial reduction in astrocyte number in FXTAS exclusively in white matter – a 38.7% reduction in the striatum and a 32.2% reduction in cerebellum (p<0.05 for both). We also found that numerous reactive astrocytes were also positive for cleaved caspase-3, suggesting that apoptosis-mediated degeneration is responsible for reduced astrocyte counts in white matter.

Conclusion: Discussion: While reactive astrogliosis is a common hallmark across neurodegenerative diseases, astrocytic degeneration is not. Since astrocytes are essential for maintaining homeostasis within the CNS, a loss of astrocytes likely further exacerbates neuropathological progression of other cell types in the FXTAS brain.
Conclusion: We have established that FXTAS neuropathology includes robust degeneration of astrocytes, which is specific to white matter.

References: N/A

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MDS Abstracts - https://www.mdsabstracts.org/abstract/fragile-x-associated-tremor-and-ataxia-syndrome-fxtas-presents-with-widespread-reactive-gliosis-and-white-matter-specific-astrocyte-degeneration/