title: Reduction of beta-amyloid-induced neurotoxicity on hippocampal cell cultures by moderate acidosis is mediated by transforming growth factor beta.
abstract: Progression of Alzheimer's disease (AD) is associated with chronic inflammation and microvascular alterations, which can induce impairment of brain perfusion because of vascular pathology and local acidosis. Acidosis can promote amyloidogenesis, which could further contribute to neurodegenerative changes. Nevertheless, there is also evidence that acidosis has neuroprotective effects in hypoxia models. Here we studied the effect of moderate acidosis on beta-amyloid (Abeta)-mediated neurotoxicity. We evaluated morphological changes, cell death, nitrite production and reductive metabolism of hippocampal cultures from Sprague-Dawley rats exposed to Abeta under physiological (pH 7.4) or moderate acidosis (pH 7.15-7.05). In addition, because transforming growth factor beta (TGFbeta) 1 is neuroprotective and is induced by several pathophysiological conditions, we assessed its presence at the different pHs. The exposure of hippocampal cells to Abeta induced a conspicuous reduction of neurites' arborization, as well as increased neuronal death and nitric oxide production. However, Abeta neurotoxicity was significantly attenuated when hippocampal cultures were kept at pH 7.15-7.05, showing a 68% reduction on lactate dehydrogenase release compared with cultures exposed to Abeta at pH 7.4 (P<0.01). Similarly, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction increased 3.5-fold (P<0.05), and Abeta-induced nitrite production was reduced by 65% when exposed to moderate acidosis compared with basal pH media (P<0.05). At the same time, moderate acidosis decreased intracellular TGFbeta1 precursor (latency associated protein-TGFbeta1) and increased up to fourfold TGFbeta1 bioactivity, detecting a 43% increase in the active TGFbeta levels in cultures exposed to Abeta and moderate acidosis. Inhibition of TGFbeta signaling abolished the neuroprotective effect of moderate acidosis. Our results show that moderate acidosis protected hippocampal cells from Abeta-mediated neurotoxicity through the increased activation and signaling potentiation of TGFbeta.
authors.affiliation: Department of Neurology, Pontificia Universidad Católica de Chile, Marcoleta 391, Santiago, Chile.
authors.forename: R
authors.initials: R
authors.lastname: Uribe-San Martín
authors.forename: R
authors.initials: R
authors.lastname: Herrera-Molina
authors.forename: L
authors.initials: L
authors.lastname: Olavarría
authors.forename: G
authors.initials: G
authors.lastname: Ramírez
authors.forename: R
authors.initials: R
authors.lastname: von Bernhardi
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D001386:Azides; D001549:Benzamides / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology; D004622:Embryo, Mammalian; D005260:Female; D006624:Hippocampus / Q000166:cytology*; D006863:Hydrogen-Ion Concentration; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013778:Tetrazolium Salts; D013844:Thiazoles / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D016229:Amyloid beta-Peptides; D001386:Azides; D001549:Benzamides; D004149:Dioxoles; D010446:Peptide Fragments; D013778:Tetrazolium Salts; D013844:Thiazoles; D016212:Transforming Growth Factor beta; D014404:Tubulin; C075222:amyloid beta-protein (1-42); D009569:Nitric Oxide; C014535:8-azidoethidium; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue