title: Amyloid-β induced astrocytosis and astrocyte death: Implication of FoxO3a-Bim-caspase3 death signaling.
abstract: 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-β (Aβ) 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 Aβ in vitro. However, how astrocytes undergo both proliferation and death in response to Aβ remains elusive. In this study, we used primary cultures of cortical astrocytes and exposed them to various doses of oligomeric Aβ. We found that cultured astrocytes proliferate and manifest all signs of astrocytosis at a low dose of Aβ. However, at high dose of Aβ the activated astrocytes undergo apoptosis. Astrocytosis was also noticed in vivo in response to Aβ in the rat brain. Next, we investigated the mechanism of astrocyte apoptosis in response to a high dose of Aβ. We found that death of astrocyte induced by Aβ requires a set of molecules that are instrumental for neuron death in response to Aβ. 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 Aβ decides whether astrocytes do proliferate or undergo apoptosis via a mechanism that is required for neuron death.
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700 032, India.
authors.forename: Pampa
authors.initials: P
authors.lastname: Saha
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700 032, India. Electronic address: biswassc@gmail.com.
authors.forename: Subhas Chandra
authors.initials: SC
authors.lastname: Biswas
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects*; D000072224:Bcl-2-Like Protein 11; D001562:Benzimidazoles / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D001562:Benzimidazoles; D002232:Carbocyanines; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D053148:Caspase 3
keywords: Alzheimer's disease; Apoptosis; Astrogliosis; Glia