REDUCTION OF beta-AMYLOID-INDUCED NEUROTOXICITY ON HIPPOCAMPAL CELL CULTURES BY MODERATE ACIDOSIS IS MEDIATED BY TRANSFORMING GROWTH FACTOR beta

Martin, RUS; Herrera-Molina, R; Olavarria, L.; Ramirez G.; von Bernhardi R.

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 ß-amyloid (Aß)-mediated neurotoxicity. We evaluated morphological changes, cell death, nitrite production and reductive metabolism of hippocampal cultures from Sprague-Dawley rats exposed to Aß under physiological (pH 7.4) or moderate acidosis (pH 7.15-7.05). In addition, because transforming growth factor ß (TGFß) 1 is neuroprotective and is induced by several pathophysiological conditions, we assessed its presence at the different pHs. The exposure of hippocampal cells to Aß induced a conspicuous reduction of neurites' arborization, as well as increased neuronal death and nitric oxide production. However, Aß 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 Aß 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 Aß-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 TGFß1 precursor (latency associated protein-TGFß1) and increased up to fourfold TGFß1 bioactivity, detecting a 43% increase in the active TGFß levels in cultures exposed to Aß and moderate acidosis. Inhibition of TGFß signaling abolished the neuroprotective effect of moderate acidosis. Our results show that moderate acidosis protected hippocampal cells from Aß-mediated neurotoxicity through the increased activation and signaling potentiation of TGFß. © 2009 IBRO.

Más información

Título según WOS: REDUCTION OF beta-AMYLOID-INDUCED NEUROTOXICITY ON HIPPOCAMPAL CELL CULTURES BY MODERATE ACIDOSIS IS MEDIATED BY TRANSFORMING GROWTH FACTOR beta
Título según SCOPUS: Reduction of ?-amyloid-induced neurotoxicity on hippocampal cell cultures by moderate acidosis is mediated by transforming growth factor ?
Título de la Revista: NEUROSCIENCE
Volumen: 158
Número: 4
Editorial: Elsevier
Fecha de publicación: 2009
Página de inicio: 1338
Página final: 1347
Idioma: English
URL: http://linkinghub.elsevier.com/retrieve/pii/S0306452208016564
DOI:

10.1016/j.neuroscience.2008.11.002

Notas: ISI, SCOPUS