# Astrocyte-synapse interactions in a rat model of Alexander disease

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $409,025

## Abstract

Project Summary
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.

## Key facts

- **NIH application ID:** 9875492
- **Project number:** 5R01NS110719-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Tracy Hagemann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,025
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875492

## Citation

> US National Institutes of Health, RePORTER application 9875492, Astrocyte-synapse interactions in a rat model of Alexander disease (5R01NS110719-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9875492. Licensed CC0.

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