Sadayuki Hashioka, James G. McLarnon and Andis Klegeris* Pages 925 - 938 ( 14 )
Astrocytes contribute to brain development and homeostasis and support diverse functions of neurons. These cells also respond to the pathological processes in Alzheimer’s disease (AD). There is still considerable debate concerning the overall contribution of astrocytes to AD pathogenesis since both the protective and harmful effects of these cells on neuronal survival have been documented. This review focuses exclusively on the neurotoxic potential of astrocytes while acknowledging that these cells can contribute to neurodegeneration through other mechanisms, for example, by lowered neurotrophic support. We identify reactive oxygen and nitrogen species, tumor necrosis factor α (TNF-α), glutamate, and matrix metalloproteinase (MMP)-9 as molecules that can be directly toxic to neurons and are released by reactive astrocytes. There is also considerable evidence suggesting their involvement in AD pathogenesis. We further discuss the signaling molecules that trigger the neurotoxic response of astrocytes with a focus on human cells. We also highlight microglia, the immune cells of the brain, as critical regulators of astrocyte neurotoxicity. Nuclear imaging and magnetic resonance spectroscopy (MRS) could be used to confirm the contribution of astrocyte neurotoxicity to AD progression. The molecular mechanisms discussed in this review could be targeted in the development of novel therapies for AD.
Reactive astrocytes, neurodegeneration, microglia, reactive oxygen species, reactive nitrogen species, tumor necrosis factor α, glutamate, matrix metalloproteinases.
Department of Psychiatry, Shimane University, Izumo, Shimane 693-8501, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, V5Z 1M9, Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia, V1V 1V7