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Amyloid beta-peptide activates nuclear factor-kappaB through an N-methyl-D-aspartate signaling pathway in cultured cerebellar cells.

Abstract：

:Amyloid beta-peptide (A beta) likely causes functional alterations in neurons well prior to their death. Nuclear factor-kappaB (NF-kappaB), a transcription factor that is known to play important roles in cell survival and apoptosis, has been shown to be modulated by A beta in neurons and glia, but the mechanism is unknown. Because A beta has also been shown to enhance activation of N-methyl-D-aspartate (NMDA) receptors, we investigated the role of NMDA receptor-mediated intracellular signaling pathways in A beta-induced NF-kappaB activation in primary cultured rat cerebellar cells. Cells were treated with different concentrations of A beta1-40 (1 or 2 microM) for different periods (6, 12, or 24 hr). MK-801 (NMDA antagonist), manumycin A and FTase inhibitor 1 (farnesyltransferase inhibitors), PP1 (Src-family tyrosine kinase inhibitor), PD98059 [mitogen-activated protein kinase (MAPK) inhibitor], and LY294002 [phosphatidylinositol 3-kinase (PI3-k) inhibitor] were added 20 min before A beta treatment of the cells. A beta induced a time- and concentration-dependent activation of NF-kappaB (1 microM, 12 hr); both p50/p65 and p50/p50 NF-kappaB dimers were involved. This activation was abolished by MK-801 and attenuated by manumycin A, FTase inhibitor 1, PP1, PD98059, and LY294002. A beta at 1 microM increased the expression of inhibitory protein I kappaB, brain-derived neurotrophic factor, inducible nitric oxide synthase, tumor necrosis factor-alpha, and interleukin-1 beta as shown by RT-PCR assays. Collectively, these findings suggest that A beta activates NF-kappaB by an NMDA-Src-Ras-like protein through MAPK and PI3-k pathways in cultured cerebellar cells. This pathway may mediate an adaptive, neuroprotective response to A beta.

journal_name

J Neurosci Res

journal_title

Journal of neuroscience research

authors

Kawamoto EM,Lepsch LB,Boaventura MF,Munhoz CD,Lima LS,Yshii LM,Avellar MC,Curi R,Mattson MP,Scavone C

doi

10.1002/jnr.21548

subject

Has Abstract

pub_date

2008-03-01 00:00:00

pages

845-60

issue

eissn

0360-4012

issn

1097-4547

journal_volume

pub_type

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Amyloid beta-peptide activates nuclear factor-kappaB through an N-methyl-D-aspartate signaling pathway in cultured cerebellar cells.