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Abstract
Proliferation of glia and immune cells is a common pathological feature of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here, to investigate the role of proliferating cells in motor neuron disease, SOD1G93A transgenic mice were treated intracerebroventicularly (ICV) with the anti-mitotic drug cytosine arabinoside (Ara-C). ICV delivery of Ara-C accelerated disease progression in SOD1G93A mouse model of ALS. Ara-C treatment caused substantial decreases in the number of microglia, NG2+ progenitors, Olig2+ cells and CD3+ T cells in the lumbar spinal cord of symptomatic SOD1G93A transgenic mice. Exacerbation of disease was also associated with significant alterations in the expression inflammatory molecules IL-1β, IL-6, TGF-β and the growth factor IGF-1.
Highlights
Amyotrophic lateral sclerosis is a fatal, adult-onset and rapidly progressing neurodegenerative disorder characterized by the selective degeneration of motor neuron in the brain and spinal cord
We have shown that the depletion of proliferating cells in the CNS of SOD1G93A mice, consisting mainly of NG2+ and Olig2+ cells as well as microglia and T-cells, caused a significant reduction in lifespan
We have previously observed that the specific and substantial ablation of proliferating microglia had no effect on motor neuron degeneration in mutant SOD1 mice [17]
Summary
Amyotrophic lateral sclerosis is a fatal, adult-onset and rapidly progressing neurodegenerative disorder characterized by the selective degeneration of motor neuron in the brain and spinal cord. Many studies have shown that expression of mutant SOD1 in glial cells such as astrocytes and microglia causes intrinsic damage, alterations in cell function and increased cytotoxic potential of these cells which can result in enhanced damage to neighboring motor neurons [6,7,8,9,10,11]. To study the specific contribution of proliferating microglia to motor neuron degeneration, we reported previously experimental elimination of these cells by Ganciclovir treatment using doubly transgenic mice SOD1G93A; CD11b-TK [17]. Ara-C treatment caused efficient elimination of various proliferating cell types but with a negative impact on disease progression
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