REDUCTION OF beta-AMYLOID-INDUCED NEUROTOXICITY ON HIPPOCAMPAL CELL CULTURES BY MODERATE ACIDOSIS IS MEDIATED BY TRANSFORMING GROWTH FACTOR beta
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Date
2009
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PERGAMON-ELSEVIER SCIENCE LTD
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 (A beta)-mediated neurotoxicity. We evaluated morphological changes, cell death, nitrite production and reductive metabolism of hippocampal cultures from Sprague-Dawley rats exposed to A beta under physiological (pH 7.4) or moderate acidosis (pH 7.15-7.05). In addition, because transforming growth factor beta (TGF beta) 1 is neuroprotective and is induced by several pathophysiological conditions, we assessed its presence at the different pHs. The exposure of hippocampal cells to A beta induced a conspicuous reduction of neurites' arborization, as well as increased neuronal death and nitric oxide production. However, A beta 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 A beta 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 A beta-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 TGF beta 1 precursor (latency associated protein-TGF beta 1) and increased up to fourfold TGF beta 1 bioactivity, detecting a 43% increase in the active TGF beta levels in cultures exposed to A beta and moderate acidosis. Inhibition of TGF beta signaling abolished the neuroprotective effect of moderate acidosis. Our results show that moderate acidosis protected hippocampal cells from A beta-mediated neurotoxicity through the increased activation and signaling potentiation of TGF beta. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.
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Keywords
Alzheimer's disease, beta-amyloid, cell death, neurodegeneration, neuroinflammation, transforming growth factor beta 1, FOCAL CEREBRAL-ISCHEMIA, IN-VITRO ISCHEMIA, ALZHEIMERS-DISEASE, NMDA RECEPTOR, GLUTAMATE NEUROTOXICITY, MICROGLIAL REACTIVITY, PRECURSOR PROTEIN, BRAIN-TISSUE, NITRIC-OXIDE, ACTIVATION