Title:Diversity and Regulation of Astrocyte Neurotoxicity in Alzheimer's Disease
Volume: 18
Issue: 12
Author(s): Sadayuki Hashioka, James G. McLarnon and Andis Klegeris*
Affiliation:
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia, V1V 1V7,Canada
Keywords:
Reactive astrocytes, neurodegeneration, microglia, reactive oxygen species, reactive nitrogen species, tumor necrosis factor α, glutamate, matrix metalloproteinases.
Abstract: 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.
