Amyloid-β induced astrocytosis and astrocyte death: Implication of FoxO3a-Bim-caspase3 death signaling

Astrocytes, the main element of the homeostatic system in the brain, are affected in various neurological conditions including Alzheimer's disease (AD). A common astrocytic reaction in pathological state is known as astrocytosis which is characterized by a specific change in astrocyte shape due to cytoskeletal remodeling, cytokine secretion and cellular proliferation. Astrocytes also undergo apoptosis in various neurological conditions or in response to toxic insults. AD is pathologically characterized by progressive deposition of amyloid-beta (A beta) in senile plaques, intraneuronal neurofibrillary tangles, synaptic dysfunction and neuron death. Astrocytosis and astrocyte death have been reported in AD brain as well as in response to A beta in vitro. However, how astrocytes undergo both proliferation and death in response to A beta remains elusive. In this study, we used primary cultures of cortical astrocytes and exposed them to various doses of oligomeric A beta. We found that cultured astrocytes proliferate and manifest all signs of astrocytosis at a low dose of A beta. However, at high dose of AS the activated astrocytes undergo apoptosis. Astrocytosis was also noticed in vivo in response to A beta in the rat brain. Next, we investigated the mechanism of astrocyte apoptosis in response to a high dose of AS. We found that death of astrocyte induced by A beta requires a set of molecules that are instrumental for neuron death in response to A beta. It involves activation of Forkhead transcription factor Foxo3a, induction of its pro-apoptotic target Bim and activation of its downstream molecule, caspase3. Hence, this study demonstrates that the concentration of A beta decides whether astrocytes do proliferate or undergo apoptosis via a mechanism that is required for neuron death. (C) 2015 Elsevier Inc. All rights reserved.