In vitro and in vivo activation of astrocytes by amyloid-beta is potentiated by pro-oxidant agents.
Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease. Age is the main risk factor for sporadic AD, which is the most prevalent type. Amyloid-beta peptide (Abeta) neurotoxicity is the proposed first step in a cascade of deleterious events leading to AD pathology and dementia. Glial cells play an important role in these changes. Astrocytes provide vital support to neurons and modulate functional synapses. Therefore, the toxic effects of Abeta on astrocytes might promote neurodegenerative changes that lead to AD. Aging reduces astrocyte antioxidant defenses and induces oxidative stress. We studied the effects of Abeta(42) on cultures of human astrocytes in the presence or absence of the following pro-oxidant agents: buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, and FeSO(4), which liberates redox active iron. Pro-oxidant conditions potentiated Abeta toxicity, as shown by the generation of free radicals, inflammatory changes, and apoptosis. Similar treatments were assessed in rats in vivo. A combination of Abeta(40) and Abeta(42) or Abeta(42) alone was infused intracerebroventricularly for 4 weeks. Other animal groups were also infused with BSO and FeSO(4). A long-term analysis that ended 4 months later showed greater cognitive impairment in the Morris water maze task, which was induced by Abeta plus pro-oxidant agent treatments. Pro-oxidant agents also potentiated brain tissue pathology. This was demonstrated in histological studies that showed highly increased astrocyte reactivity in AD-vulnerable areas, Abeta deposits, and oxidative damage of AD-sensitive hippocampal neurons. To increase our understanding of AD, experimental models should be used that mimic age-related brain changes, in which age-related oxidative stress potentiates the effects of Abeta.
García-Matas
Silvia
S
Department Isquèmia Cerebral i Neurodegeneració, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain.
de Vera
Núria
N
Aznar
Arantxa Ortega
AO
Marimon
Josep M
JM
Adell
Albert
A
Planas
Anna M
AM
Cristòfol
Rosa
R
Sanfeliu
Coral
C
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002452:Cell Count / Q000379:methods; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005296:Ferrous Compounds / Q000494:pharmacology*; D005333:Fetus; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009573:Nitrites / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
D016229:Amyloid beta-Peptides; D016207:Cytokines; D005296:Ferrous Compounds; D005904:Glial Fibrillary Acidic Protein; D009573:Nitrites; D016877:Oxidants; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D019328:Buthionine Sulfoximine; D006861:Hydrogen Peroxide