Reversible Random Coil-.beta.-Sheet Transition of the Alzheimer .beta.-Amyloid Fragment (25-35)

Terzi, Evelyne; Hölzemann, Günter; Seelig, Joachim

doi:10.1021/bi00172a009

Cited by 149 publications

(241 citation statements)

References 22 publications

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“…For H17 (10 M), the ␤-sheet content is estimated as ϳ30% according to Greenfield and Fasman (29) in good agreement with computer simulations using the method of Yang et al (28). The concentration of monomers in solution, C A , is evaluated according to (36).…”

Section: Resultsmentioning

confidence: 99%

Phospholipid Binding of Synthetic Talin Peptides Provides Evidence for an Intrinsic Membrane Anchor of Talin

Seelig

Blatter

Frentzel

et al. 2000

Journal of Biological Chemistry

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Talin, an actin-binding protein, is assumed to anchor at the membrane via an intrinsic amino acid sequence. Three N-terminal talin fragments, 21-39 (S19), 287-304 (H18), and 385-406 (H17) have been proposed as potential membrane anchors. The interaction of the corresponding synthetic peptides with lipid model systems was investigated with CD spectroscopy, isothermal titration calorimetry, and monolayer expansion measurements. The membrane model systems were neutral or negatively charged small unilamellar vesicles or monolayers with a lateral packing density of bilayers (32 mN/ m). S19 partitions into charged monolayers/bilayers with a penetration area A p ‫؍‬ 140 ؎ 30 Å 2 and a free energy of binding of ⌬G 0 ‫؍‬ ؊5.7 kcal/mol, thereby forming a partially ␣-helical structure. H18 does not interact with lipid monolayers or bilayers. H17 penetrates into neutral and charged monolayers/bilayers with A p ‫؍‬ 148 ؎ 23 Å 2 and A p ‫؍‬ 160 ؎ 15 Å 2 , respectively, forming an ␣-helix in the membrane-bound state. Membrane partitioning is mainly entropy-driven. Under physiological conditions the free energy of binding to negatively charged membranes is ⌬G 0 ‫؍‬ ؊9.4 kcal/mol with a hydrophobic contribution of ⌬G h ‫؍‬ ؊7.8 kcal/mol, comparable to that of post-translationally attached membrane anchors, and an electrostatic contribution of ⌬G h ‫؍‬ ؊1.6 kcal/mol. The latter becomes more negative with decreasing pH. We show that H17 provides the binding energy required for a membrane anchor.Talin is a widespread actin-binding protein present in focal cell adhesions and ruffling membranes of moving cells (1, 2). In fibroblasts, talin binding to lipid membranes is associated with the establishment of a signaling cascade, mediated either by integrins (3, 4) leading to the formation of focal adhesions or, alternatively, by layilin (5) leading to a nucleation of actin assembly in membrane ruffles. In platelets, talin redistributes from the cytoplasm to the membrane during activation (6) where it colocalizes with the GPIIb/IIIa complex (7). Talin analogues have been identified in lower organisms like Dictyostelium (8) and Caenorhabditis elegans (9), the N termini and C termini being most preserved.Reasons to assume that talin is involved in a polarized assembly of the actin cytoskeleton by nucleating actin filament growth at lipid interfaces (10, 11) were provided from the finding that Dictyostelium mutants, which lack the entire protein, are massively impaired in adhesion and motility (12), and HeLa cells, when down-regulated in talin expression by antisense RNA, exhibit a reduced rate in cell spreading (13). Antibodies directed against talin, when microinjected were shown to inhibit fibroblast migration (14).Some of talin's functions have been attributed to specific protein domains. Calpain or thrombin cleavage in vitro yields two parts with 190 and 47 kDa, respectively. The C-terminal 190-kDa portion was shown to carry the actin binding sites (15) in form of a conserved sequence, the (I/L)WEQ module (16), and to be responsible f...

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Section: Resultsmentioning

confidence: 99%

Phospholipid Binding of Synthetic Talin Peptides Provides Evidence for an Intrinsic Membrane Anchor of Talin

Seelig

Blatter

Frentzel

et al. 2000

Journal of Biological Chemistry

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“…1B). Ab25-35 does not occur naturally but has shown to mimic the effects of Ab1-42 [15][16][17]. Ab1-42, which occurs in a brain affected by AD, was more effective in cell proliferation than Ab25-35 (Fig.…”

Section: Ab Promotes Microglial Cell Proliferationmentioning

confidence: 98%

Amyloid‐β peptides induce cell proliferation and macrophage colony‐stimulating factor expression via the PI3‐kinase/Akt pathway in cultured Ra2 microglial cells

et al. 2005

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AlzheimerÕs disease is characterized by numerous amyloid-b peptide (Ab) plaques surrounded by microglia. Here we report that Ab induces the proliferation of the mouse microglial cell line Ra2 by increasing the expression of macrophage colony-stimulating factor (M-CSF). We examined signal cascades for Ab-induced M-CSF mRNA expression. The induction of M-CSF was blocked by a phosphatidylinositol 3 kinase (PI3-kinase) inhibitor (LY294002), a Src family tyrosine kinase inhibitor (PP1) and an Akt inhibitor. Electrophoretic mobility shift assays showed that Ab enhanced NF-jB binding activity to the NF-jB site of the mouse M-CSF promoter, which was blocked by LY294002. These results indicate that Ab induces M-CSF mRNA expression via the PI3-kinase/Akt/NF-jB pathway.

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“…The initial neuronal responses to A␤ in cortical circuits and the regulation of A␤-induced signaling remain unclear. In this study, we found that exposure of cortical slices to A␤ or A␤ [25][26][27][28][29][30][31][32][33][34][35] induced a marked increase in the activation of protein kinase C (PKC) and Ca 2؉ /calmodulin-dependent kinase II (CaMKII), two enzymes critically involved in a variety of cellular functions. Activation of M1 muscarinic receptors, but not nicotinic receptors, significantly inhibited the A␤ activation of PKC and CaMKII.…”

mentioning

confidence: 99%

Activation of Muscarinic Receptors Inhibits औ-Amyloid Peptide-induced Signaling in Cortical Slices

Zhong

Yan

2003

Journal of Biological Chemistry

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Deposition of fibrillar aggregates of the ␤-amyloid peptide (A␤) is a key pathologic feature during the early stage of Alzheimer's disease. The initial neuronal responses to A␤ in cortical circuits and the regulation of A␤-induced signaling remain unclear. In this study, we found that exposure of cortical slices to A␤ 1-42 or A␤ 25-35 induced a marked increase in the activation of protein kinase C (PKC) and Ca 2؉ /calmodulin-dependent kinase II (CaMKII), two enzymes critically involved in a variety of cellular functions. Activation of M1 muscarinic receptors, but not nicotinic receptors, significantly inhibited the A␤ activation of PKC and CaMKII. Increasing inhibitory transmission mimicked the M1 effect on A␤, whereas blocking GABA A receptors eliminated the M1 action. Moreover, electrophysiological evidence shows that application of A␤ to cortical slices induced action potential firing and enhanced excitatory postsynaptic currents, whereas muscarinic agonists potently increased inhibitory postsynaptic currents. These results suggest that A␤ activates PKC and CaMKII through enhancing excitatory activity in glutamatergic synaptic networks. Activation of M1 receptors inhibits A␤ signaling by enhancing the counteracting GABA ergic inhibitory transmission. Thus the muscarinic reversal of the A␤-induced biochemical and physiological changes provides a potential mechanism for the treatment of Alzheimer's disease with cholinergic enhancers.The 40 -42-amino acid ␤-amyloid peptide (A␤) 1 is a major constituent of senile plaques (1), extracellular protein aggregates that are used as a histopathological hallmark for the diagnosis of Alzheimer's disease (AD). Emerging evidence has suggested that A␤ makes a direct contribution to the pathogenesis of AD (2, 3). A␤ peptides are produced by the cleavage of ␤-amyloid precursor protein (APP) (4). Mutations in the APP gene increases the rate of cleavage, thereby leading to the overproduction of A␤ (5, 6). Transgenic mice overexpressing mutant APP genes exhibit AD-like A␤ deposits and cognition impairments (7-9). In vitro studies in cell lines and cultured neurons show that fibrillar A␤ is neurotoxic at high concentrations (10, 11), and most strikingly, A␤ exposure renders neurons more vulnerable to excitatoxicity (12, 13). Although intensive efforts have been concentrated on factors affecting A␤ production, aggregation, and metabolism (14, 15), little is known about the earliest biochemical and physiological changes in neurons in response to the subtoxic concentrations of A␤, which may be critical for subsequent neurodegenerative changes and the factors that can regulate the A␤-initiated signaling.In addition to A␤ deposits, a prominent feature of AD is the degeneration of basal forebrain cholinergic neurons and ensuing deficient cholinergic functions in their target areas including cortex and hippocampus (16 -18). Despite an improved understanding of the critical role of the cholinergic system in normal cognition and dementia (19,20), it has been largely unclear how cholinergic ...

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Reversible Random Coil-.beta.-Sheet Transition of the Alzheimer .beta.-Amyloid Fragment (25-35)

Cited by 149 publications

References 22 publications

Phospholipid Binding of Synthetic Talin Peptides Provides Evidence for an Intrinsic Membrane Anchor of Talin

Phospholipid Binding of Synthetic Talin Peptides Provides Evidence for an Intrinsic Membrane Anchor of Talin

Amyloid‐β peptides induce cell proliferation and macrophage colony‐stimulating factor expression via the PI3‐kinase/Akt pathway in cultured Ra2 microglial cells

Activation of Muscarinic Receptors Inhibits औ-Amyloid Peptide-induced Signaling in Cortical Slices

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