Bi-phasic gliosis drives neuropathology in a Sandhoff disease mouse model

• We observe a two-stage process of inflammation/neurodegeneration in Sandhoff disease.
• Microgliosis precedes astrogliosis and apoptosis in Sandhoff disease.
• GluR1 is reduced by 80 days in the cerebella of Sandhoff disease mice.

Microgliosis and astrogliosis are known to be exacerbating factors in the progression of the lysosomal storage disorder Sandhoff disease. We have also found evidence for excitotoxicity via glutamate receptors in Sandhoff disease. To view the interaction of these cascades, we measured cerebellar expression of markers for gliosis, apoptosis, and excitatory synapses over the disease course in a Sandhoff disease mouse model. We observe a 2-stage model, with initial activation of microgliosis as early as 60 days of age, followed by a later onset of astrogliosis, caspase-mediated apoptosis, and reduction in GluR1 at approximately 100 days of age. These results implicate immune cells as first responders in Sandhoff disease.