Rapid impact of ?-amyloid on Paxillin in a neural cell line

Abstract

Beta-amyloid1-42 (Abeta) is a naturally occuring peptide whose accumulation in the brain is putatively coupled to Alzheimer's disease pathogenesis. Deleterious effects of Abeta on neurons have been linked to the inappropriate activation of signaling pathways within the cell (reviewed in Yankner, 1996), including tyrosine phosphorylation of focal adhesion kinase (FAK) (Zhang et al., 1994, 1996a,b). Here we have investigated the effects of Abeta on paxillin in a neural cell line. Paxillin, a substrate for FAK, is thought to act as a signal "integrator," functioning to link other proteins into multi-molecular signaling complexes (reviewed in Turner, 1994). Treatment of the rat central nervous system B103 cell line with aggregates of Abeta was found to induce the tyrosine phosphorylation of paxillin within 30 min, nearly 24 hr prior to significant cell death. Particularly striking was a subsequent "mobilization" of paxillin to the cytoskeleton in Abeta-treated cells. The amount of paxillin associated with the cytoskeleton in Abeta-treated cells was increased 10-fold over controls. The Abeta-induced paxillin accumulation could be visualized immunocytochemically, with an increase in number and size of paxillin-labeled focal contacts upon treatment with Abeta. This effect was specific, in that vinculin, another focal contact protein, was unaffected by Abeta. Disruption of f-actin, which inhibits both Abeta-induced neurotoxicity (Furukawa and Mattson, 1995) and focal contact signaling in B103 cells (Zhang et al., 1996b) was found to block the cytoskeletal paxillin accumulation. The rapid tyrosine phosphorylation and cytoskeletal mobilization of paxillin links Abeta to the activation of focal contact signaling events that may influence neuronal cytoskeletal architecture, gene expression, synaptic plasticity and cell viability.

Aberrant Activation of Focal Adhesion Proteins Mediates Fibrillar Amyloid β-Induced Neuronal Dystrophy

“…1C,D). This result is consistent with previous reports showing the activation of Tyr kinase activity and increased paxillin Tyr phosphorylation in neuronal cells treated with fibrillar A␤ (Berg et al, 1997;Williamson et al, 2002). Paxillin translocation to the cytoskeleton was assessed by Western blot of whole-cell homogenates and cytoskeletal preparations.…”

“…In this regard, fibrillar A␤ could promote dystrophy by aberrantly activating signal transduction cascades leading to cytoskeletal changes (Saitoh et al, 1993). A␤ binds to integrins (Kowalska and Badellino, 1994;Sabo et al, 1995;Goodwin et al, 1997) and activates the focal adhesion (FA) proteins paxillin and focal adhesion kinase (FAK), which are downstream of integrin receptors, suggesting that FA signaling cascades might be involved in A␤-induced neuronal dystrophy, cell death, or both (Zhang et al, 1994(Zhang et al, , 1996Berg et al, 1997;Williamson et al, 2002). To address the role of FA signaling in A␤-induced neuronal dystrophy, we analyzed the expression and activity of FA proteins in the AD brain and in cultured neurons exposed to fibrillar A␤.…”

Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins

“…Previous studies in nonneuronal cells have shown that both Ca 2ϩ and ROS are relevant to signaling via Src family protein tyrosine kinases (59)(60)(61). In neuronal cells, toxicity of traditional A␤ preparations also has been linked to transduction molecules associated with focal contact signaling (32,62,63), a cascade that includes Fyn (41). In B103 cells, ADDLs have been found to stimulate Fyn kinase Ϸ2-fold within 30 min (C.Z.…”

Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers

“…Although previous studies suggest that activation of PI3K/Akt may protect against neuronal death induced by Aβ [e.g. 3,37], those same signaling pathways also have been reported to be activated by Aβ [e.g., 5,16,21,57]. Therefore, it is possible that ADDL binding to neuronal target receptors leads to aberrant activation of trophic signaling and to an incomplete set of downstream events that lead to tau hyperphosphorylation and neuronal dysfunction.…”