Aβ1-42 stimulates actin polymerization in hippocampal neurons through Rac1 and CDC42 Rho GTPases

University of Santiago, Chile, CiudadSantiago, Santiago Metropolitan, Chile
Journal of Cell Science (Impact Factor: 5.43). 02/2007; 120(Pt 2):279-88. DOI: 10.1242/jcs.03323
Source: PubMed


A number of psychiatric and neurodegenerative disorders, such as Alzheimer's disease, are characterized by abnormalities in the neuronal cytoskeleton. Here, we find that the enhancement in actin polymerization induced by fibrillar amyloid-beta peptide (Abeta) is associated with increased activity of Rac1/Cdc42 Rho GTPases. Rac1 upregulation involves the participation of Tiam1, a Rac guanine-nucleotide exchange factor, where Abeta exposure leads to Tiam1 activation by a Ca(2+)-dependent mechanism. These results point to Rho GTPases as one of the targets in Abeta-induced neurodegeneration in Alzheimer's disease pathology, with a role in mediating changes in the actin cytoskeletal dynamics.

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Available from: Christian González-Billault, Aug 14, 2015
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    • "The Rho family of GTPases such as Rac1, RhoA, and Cdc42 are major regulators of synaptic plasticity, acting on dendrite morphogenesis and stability, growth cone motility and collapse (Ramakers 2002; Sekino et al. 2007; Linseman and Loucks 2008) and affecting neuronal architecture and synaptic connectivity (Pilpel and Segal 2004). There are data indicating that certain small Rho family GTPases such as Rac1, RhoA, and Cdc42 contribute to AD pathogenesis (D esir e et al. 2005; Mendoza-Naranjo et al. 2007; Ma et al. 2008; Wang et al. 2009; Huesa et al. 2010; Oh et al. 2010). "
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    ABSTRACT: High serum/plasma cholesterol levels have been suggested as a risk factor for Alzheimer disease (AD). Some reports, mostly retrospective epidemiological studies, have observed a decreased prevalence of AD in patients taking the cholesterol lowering drugs, statins. The strongest evidence causally linking cholesterol to AD is provided by experimental studies showing that adding/reducing cholesterol alters amyloid precursor protein (APP) and amyloid beta-protein (Aβ) levels. However, there are problems with the cholesterol-AD hypothesis. Cholesterol levels in serum/plasma and brain of AD patients do not support cholesterol as a causative factor in AD. Prospective studies on statins and AD have largely failed to show efficacy. Even the experimental data are open to interpretation given that it is well-established that modification of cholesterol levels has effects on multiple proteins, not only APP and Aβ. The purpose of this review, therefore, is to examine the above-mentioned issues and discuss the pros and cons of the cholesterol-AD hypothesis, and the involvement of other lipids in the mevalonate pathway, such as isoprenoids and oxysterols, in AD. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 12/2013; 129(4). DOI:10.1111/jnc.12637 · 4.28 Impact Factor
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    • "The activation of Rac1 is controlled by guanine nucleotide-exchange factors (GEFs) including ␤PIX, which binds to Rac1 and stimulates GDP/GTP exchange (Manser et al., 1998; Raftopoulou and Hall, 2004; Zhang et al., 2005). Various neurological disorders evoked by deficits in cytoskeleton dynamics have been linked to Rac1 and ␤PIX (Colomer et al., 1997; Fiala et al., 2002; Kutsche et al., 2000; Mendoza-Naranjo et al., 2007; Newey et al., 2005; Zhang et al., 2005), suggesting that alterations in function may cause abnormal signaling and loss of cytoskeleton structure. Scribble is a peripheral membrane protein, which belongs to the LAP (leucine rich-repeats and PDZ) protein family including mammalian Erbin and Densin-180 (Zhang et al., 2006). "
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    ABSTRACT: Neurite outgrowth is mediated by dynamic changes of the cytoskeleton and is largely controlled by Rho GTPases and their regulators. Here, we show that the polarity protein Scribble controls PC12 cell neurite outgrowth in response to nerve growth factor. Scribble knockdown decreases neurite numbers and increases neurite length. This effect is linked to TrkA the cognate receptor for NGF as pharmacological inhibition of phosphorylated TrkA (pTrkA) reduces Scribble expression. Moreover, Scribble forms a complex with the MAPK components ERK1/2 in a growth factor dependent manner. In RNAi experiments where Scribble expression is efficiently depleted sustained ERK1/2 phosphorylation is reduced. Conversely, siRNA with intermediate Scribble silencing efficiency fails to match this effect indicating that ERK1/2 activation depends on basic Scribble protein levels. Finally, Scribble translocates to the plasma membrane in response to growth factor where it complexes with HRas and Rac1 suggesting that the phenotype activated by loss of Scribble may be a result of altered GTPase activity. Together, these results demonstrate a novel role for Scribble in neurite outgrowth of PC12 cells.
    European journal of cell biology 07/2013; 92(6-7). DOI:10.1016/j.ejcb.2013.07.002 · 3.83 Impact Factor
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    • "Aβ1–42 has been reported to enhance actin polymerization and induce actin stress fiber formation in neuronal cells. [22], [23]. Since the organization of cytoskeleton governs cell mechanics and adhesion, we employed QIM of F-actin labeled with Oregon green phalloidin to quantify actin polymerization induced by Aβ1–42 in CECs. "
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    ABSTRACT: Increased deposition of amyloid-β peptide (Aβ) at the cerebral endothelial cell (CEC) surface has been implicated in enhancement of transmigration of monocytes across the brain blood barrier (BBB) in Alzheimer's disease (AD). In this study, quantitative immunofluorescence microscopy (QIM) and atomic force microscopy (AFM) with cantilevers biofunctionalized by sialyl-Lewis(x) (sLe(x)) were employed to investigate Aβ-altered mechanics of membrane tethers formed by bonding between sLe(x) and p-selectin at the CEC surface, the initial mechanical step governing the transmigration of monocytes. QIM results indicated the ability for Aβ to increase p-selectin expression at the cell surface and promote actin polymerization in both bEND3 cells (immortalized mouse CECs) and human primary CECs. AFM data also showed the ability for Aβ to increase cell stiffness and adhesion probability in bEND3 cells. On the contrary, Aβ lowered the overall force of membrane tether formation (Fmtf ), and produced a bimodal population of Fmtf , suggesting subcellular mechanical alterations in membrane tethering. The lower Fmtf population was similar to the results obtained from cells treated with an F-actin-disrupting drug, latrunculin A. Indeed, AFM results also showed that both Aβ and latrunculin A decreased membrane stiffness, suggesting a lower membrane-cytoskeleton adhesion, a factor resulting in lower Fmtf . In addition, these cerebral endothelial alterations induced by Aβ were abrogated by lovastatin, consistent with its anti-inflammatory effects. In sum, these results demonstrated the ability for Aβ to enhance p-selectin expression at the CEC surface and induce cytoskeleton reorganization, which in turn, resulted in changes in membrane-cytoskeleton adhesion and membrane tethering, mechanical factors important in transmigration of monocytes through the BBB.
    PLoS ONE 04/2013; 8(4):e60972. DOI:10.1371/journal.pone.0060972 · 3.23 Impact Factor
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