Amyloid Abeta1-40 preconditions non-apoptotic signals in vivo and protects fetal rat brain from intrauterine ischemic stress.
Abstract The dualistic activities of the amyloid beta (Abeta) peptide as a pro-oxidant and ubiquitous constituent of amyloid deposits in Alzheimer's disease plaques and as an antioxidant of purported physiological function has been suggested but the mechanisms are far from being understood. In this report we measure several oxidative stress parameters and signaling cascades in brains of fetal rats subjected to global ischemia in order to evaluate the putative bifunctional properties of the Abeta(1-40) peptide. Intraperitoneal injection of 6 microg Abeta(1-40) into 18-days-old rat fetuses (approximately 3 g body weight) resulted after 24 h in the appearance of the peptide in various fetal organs including brain where it enhanced the levels of glutathione (GSH), glutathione reductase, glutathione peroxidase, and stimulated the levels of pro-survival signaling activities such as Akt serine/threonine kinase, extracellular signal-regulated kinase (ERK) and protein kinase C enzymes. Moreover, pretreatment with Abeta(1-40) reversed the consequences of a transient hypovolemic/hypotensive oxidative stress by restoring GSH levels via its recycling enzymes and by lowering the production of lipid peroxides presumably by activating the aforementioned pro-survival signaling cascades. It also caused a reduction in the number of DAPI-enhanced reactive cells and a decrease in p38 kinase phosphorylation and caspase-9 and -3 activity. These data suggest that pre-exposure to Abeta(1-40) stimulates fetal tolerance to ischemia via regulation of GSH metabolism and as such may be considered as neuroprotective.
Kuperstein
Faina
F
Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.
Brand
Annette
A
Yavin
Ephraim
E
D016229:Amyloid beta-Peptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005333:Fetus; D007022:Hypotension / Q000503:physiopathology; D020896:Hypovolemia / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D008431:Maternal-Fetal Exchange / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D020169:Caspases