Alexander disease (AxD) is a fatal neurodegenerative disease caused by mutations in the gene for glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes, which lead to protein aggregation and a reactive astrocyte response. AxD is classified into two subtypes, with the more severe Type I patients having early onset with cognitive and motor delays, seizures, and failure to thrive. Existing mouse models have been integral in elucidating pathways and mechanisms in AxD astrocyte pathology, but display minimal clinical deficits compared to the human disease. We have developed a new GFAP mutant rat model that exhibits precipitous decline just after the third postnatal week, and preliminary data demonstrate significant cognitive and motor impairment and the potential loss of neurons in adult animals. This new model offers unique opportunities to investigate the contribution of abnormal astrocyte-neuron interaction in AxD, particularly with respect to synapses and neuron number.
In Specific Aim 1, we will determine when astrocytes begin to react to mutant GFAP and whether this coincides with protein aggregation through both molecular and ultrastructural analysis. The effects of GFAP pathology on astrocyte maturation and survival will be assessed by quantifying neuropil infiltration during postnatal development, and astrocyte numbers in juvenile and adult rats.
In Specific Aim 2, we will examine the effects of astrocyte pathology on postnatal synaptogenesis and neuronal survival by quantifying synapse formation, maturation, and elimination, as well as numbers of neurons in juvenile and adult animals. To further define the effects of astrocyte dysfunction on neurons in AxD, we will perform transcription profiling with acutely isolated astrocytes (Aim 1) and neurons (Aim 2) at different stages of disease development. These data will be used to assess synaptogenic cues and the balance of inflammatory and protective pathways, and to correlate the potential loss of normal astrocyte functions in synaptic support throughout disease progression.
In Specific Aim 3, juvenile animals will be tested to determine whether cognitive and motor impairment are apparent before the onset of severe clinical phenotypes. Finally, we will use antisense technology to test rescue of neuronal and cognitive phenotypes at early and late stages of disease by GFAP suppression. This work will identify new features of pathogenesis, improve our understanding of the secondary changes in neurons, and test the reversibility of these phenotypes at different stages of disease.
We are studying the rare disorder Alexander disease as a model to understand the role of astrocytes in the brain, under both normal conditions and in disease. Our long-term goal is to develop novel ways of restoring astrocyte function when they are impaired.