Amyloid β‐peptide activates nuclear factor‐κB 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.

Intermittent fasting attenuates lipopolysaccharide-induced neuroinflammation and memory impairment

“…Because BDNF plays critical roles in hippocampal synaptic plasticity and cognitive function, it is likely that maintenance of BDNF signaling contributes to the beneficial effects of IF on cognitive function in LPS-treated rats. Previous studies have provided evidence that BDNF is a key target of NF-κB involved in NMDA receptor-mediated cell survival signaling [89-92] and IF has been shown to activate glutamate signaling cascade in the CNS [58]. The ability of IF to suppress inflammatory processes and sustain hippocampal BDNF levels in the face of systemic inflammation, suggests that IF interventions should be evaluated in studies of human subjects at risk for or suffering from neurological conditions involving neuroinflammation.…”

Role of Glutamate and NMDA Receptors in Alzheimer’s Disease

“…In general, species of Aβ causes elevated NMDAR-mediated synaptic currents and collateral toxicity, which can be attenuated or blocked by NMDAR antagonists, such as MK-801 (Le, Colom et al 1995, Domingues, Almeida et al 2007, Kawamoto, Lepsch et al 2008), D-APV or memantine (Kamenetz, Tomita et al 2003, Ye, Walsh et al 2004, Alberdi, Sanchez-Gomez et al 2010, Texido, Martin-Satue et al 2011). The structural effects of Aβ, such as synaptic loss, can also be prevented by NMDAR antagonists (Hsieh, Boehm et al 2006, Shankar, Bloodgood et al 2007).…”

Amyloid-β as a Modulator of Synaptic Plasticity

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