1–42 β-Amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death

Abstract

1–42 β-Amyloid (Aβ1–42) peptide is a key molecule involved in the development of Alzheimer's disease. Some of its effects are manifested at the neuronal morphological level. These morphological changes involve loss of neurites due to cytoskeleton alterations. However, the mechanism of Aβ1–42 peptide activation of the neurodegenerative program is still poorly understood. Here, Aβ1–42 peptide-induced transduction of cellular death signals through the phosphatidylinositol 3-kinase (PI3K)/phosphoinositol-dependent kinase (PDK)/novel protein kinase C (nPKC)/Rac 1 axis is described. Furthermore, pharmacological inhibition of PDK1 and nPKC activities blocks Rac 1 activation and neuronal cell death. Our results provide insights into an unsuspected connection between PDK1, nPKCs and Rac 1 in the same signal-transduction pathway and points out nPKCs and Rac 1 as potential therapeutic targets to block the toxic effects of Aβ1–42 peptide in neurons.

PDK1 Determines Collagen-Dependent Platelet Ca 2+ Signaling and Is Critical to Development of Ischemic Stroke In Vivo

“…Because PDK1 has been reported to modify actin cytoskeleton reorganization and to act as potential regulator of Rac1 in neuronal cells, 24,29 we elucidated the role of PDK1-dependent signaling in collagen-induced lamellipodia formation and platelet spreading. According to Rac1 activation assay ( Figure 3A), stimulation of pdk1 fl/fl platelets with increasing concentrations of CRP resulted in a rapid and strong increase of Rac1-GTP binding, illustrating Rac1 activation, an effect significantly blunted in pdk1 −/− platelets, indicating that PDK1/Akt signaling is involved in platelet Rac1 activation downstream of GPVI after stimulation with CRP.…”

“…These findings are in line with broad evidence from other cells and diseases showing that Rac1 is activated by PI3K/Akt-dependent signaling 47 and with a recent study identifying Rac1 as a downstream target of PDK1. 29 As suggested by comparison with platelets isolated from rac1 −/− mice,…”

Guanine Nucleotide Exchange Factor αPIX Leads to Activation of the Rac 1 GTPase/Glycogen Phosphorylase Pathway in Interleukin (IL)-2-stimulated T Cells

“…In some experiments, Kit 225 T cells were pretreated with 10 M H-89 (PKA inhibitor) or 20 M LY29004 (PI3K inhibitor) or 100 nM Gö6976 and different concentrations of Rottlerin (PKC inhibitors) for 1 h prior to IL-2 or PMA stimulation (13,42).…”

Common Mechanisms of Alzheimer's Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration

“…Novel PKC isoforms, including PKCδ and PKCθ, are heavily involved in mediating Aβ 42 processing. Aβ 42 triggers changes in phosphatidylinositol 3-kinase, phosphoinositol-dependent kinase, and Rac 1 that ultimately result in cell lysis and the release of reactive oxygen species [124]. It is not yet known if the increase in novel isoforms is strictly an age-dependent adjustment or an indication of accumulated neural injuries.…”