The Receptor-Bound N-Terminal Ectodomain of the Amyloid Precursor Protein Is Associated with Membrane Rafts

Tikkanen, Ritva; Icking, Ann; Beicht, Peter; Waneck, Gerald L.; Herzog, Volker

doi:10.1515/bc.2002.209

Cited by 9 publications

(7 citation statements)

References 47 publications

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“…This finding suggests that interaction between the antibody and APP may mimic receptor cross-linking and thus disrupt signal transduction mechanisms mediated by APP. The notion that both APP and the membrane binding sites for sAPP␣ primarily reside in lipid raft microdomains (Tikkanen et al, 2002;Ehehalt et al, 2003) suggests the possibility that sAPP␣ interacts with APP through either homophilic interaction or indirectly with as yet unidentified functional ligands and thus acts in trans to transduce signals. Moreover, a synergistic mechanism has also been suggested to involve upregulation of common survival pathways (e.g., phosphatidylinositol 3-kinase/Akt) (Cheng et al, 2002) and anti-apoptotic factors (Bcl-2 and X-linked inhibitor of apoptosis protein) (our unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Cyclin-Dependent Kinase 5 Activation by Amyloid Precursor Protein: A Novel Excitoprotective Mechanism Involving Modulation of Tau Phosphorylation

Han¹,

Dou²,

Feng³

et al. 2005

J. Neurosci.

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Alzheimer's disease is cytopathologically characterized by loss of synapses and neurons, neuritic amyloid plaques consisting of ␤-amyloid (A␤) peptides, and neurofibrillary tangles consisting of hyperphosphorylated tau protein in susceptible brain regions. A␤, which triggers a cascade of pathogenic events including tau phosphorylation and neuronal excitotoxicity, is proteolytically derived from ␤-amyloid precursor protein (APP); the pathological and physiological functions of APP, however, remain undefined. Here we demonstrate that the level of tau phosphorylation in cells and brains deficient in APP is significantly higher than that in wild-type controls, resulting from activation of cyclin-dependent kinase 5 (CDK5) but not glycogen synthase kinase 3, the two major tau kinases. In addition, we show that overexpression of APP or its non-amyloidogenic homolog amyloid precursor-like protein 1 suppresses both basal and stress-induced CDK5 activation. The ectodomain of APP, sAPP␣, is responsible for inhibiting CDK5 activation. Furthermore, neurons derived from APP-deficient mice exhibit reduced metabolism and survival rates and are more susceptible to excitotoxic glutamateinduced apoptosis. These neurons also manifest significant defects in neurite outgrowth compared with neurons from the wild-type littermates. The observed neuronal excitotoxicity/apoptosis is mediated through a mechanism involving CDK5 activation. Our study defines a novel neuroprotective function for APP in preventing tau hyperphosphorylation via suppressing overactivation of CDK5. We suggest that CDK5 activation, through a calcium/calpain/p25 pathway, plays a key role in neuronal excitotoxicity and represents an underlying mechanism for the physiological functions of APP.

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Section: Discussionmentioning

confidence: 99%

Suppression of Cyclin-Dependent Kinase 5 Activation by Amyloid Precursor Protein: A Novel Excitoprotective Mechanism Involving Modulation of Tau Phosphorylation

Han¹,

Dou²,

Feng³

et al. 2005

J. Neurosci.

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“…The Ab-bearing Cterminal fragment produced by b-secretase (134, 138), the APP N-terminal fragment (139), and Abs (129,140,141) have been identified in lipid rafts of cultured cells and mammalian brains. a-Secretase (135, 142-144), b-secretase (BACE1, Asp-2, memapsin-1) (21,141,143,145,146), and PSEN1(g-secretase) (129,133,134,138,147), apoE, and tau are also known to be present in lipid rafts (141).…”

Section: Ad-related Components In Membrane Microdomains or Lipid Raftsmentioning

confidence: 99%

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

Ariga

McDonald

2008

Journal of Lipid Research

292

236

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“…There is also considerable evidence for involvement of cholesterol in APP processing. The N-terminal ectodomain of APP fractionates with cholesterolrich membrane rafts (86). Altering the subcellular distribution of cholesterol by inhibiting intracellular cholesterol transport reduces the cleavage of APP by ␤-secretases (87).…”

Section: Figmentioning

confidence: 99%

Oxidation of Cholesterol by Amyloid Precursor Protein and β-Amyloid Peptide

Nelson

Alkon

2005

Journal of Biological Chemistry

178

129

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Alzheimer's disease (AD) is characterized by accumulation of the neurotoxic peptide ␤-amyloid, which is produced by proteolysis of amyloid precursor protein (APP). APP is a large membrane-bound copper-binding protein that is essential in maintaining synaptic function and may play a role in synaptogenesis. ␤-Amyloid has been shown to contribute to the oxidative stress that accompanies AD. Later stages of AD are characterized by neuronal apoptosis. However, the biochemical function of APP and the mechanism of the toxicity of ␤-amyloid are still unclear. In this study, we show that both ␤-amyloid and APP can oxidize cholesterol to form 7␤-hydroxycholesterol, a proapoptotic oxysterol that was neurotoxic at nanomolar concentrations. 7␤-Hydroxycholesterol inhibited secretion of soluble APP from cultured rat hippocampal H19 -7/IGF-IR neuronal cells and inhibited tumor necrosis factor-␣-converting enzyme ␣-secretase activity but had no effect on ␤-site APPcleaving enzyme 1 activity. 7␤-Hydroxycholesterol was also a potent inhibitor of ␣-protein kinase C, with a K i of ϳ0.2 nM. The rate of reaction between cholesterol and ␤-amyloid was comparable to the rates of cholesterolmetabolizing enzymes (k cat ‫؍‬ 0.211 min ؊1 ). The rate of production of 7␤-hydroxycholesterol by APP was ϳ200 times lower than by ␤-amyloid. Oxidation of cholesterol was accompanied by stoichiometric production of hydrogen peroxide and required divalent copper. The results suggest that a function of APP may be to produce low levels of 7-hydroxycholesterol. Higher levels produced by ␤-amyloid could contribute to the oxidative stress and cell loss observed in Alzheimer's disease.

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The Receptor-Bound N-Terminal Ectodomain of the Amyloid Precursor Protein Is Associated with Membrane Rafts

Cited by 9 publications

References 47 publications

Suppression of Cyclin-Dependent Kinase 5 Activation by Amyloid Precursor Protein: A Novel Excitoprotective Mechanism Involving Modulation of Tau Phosphorylation

Suppression of Cyclin-Dependent Kinase 5 Activation by Amyloid Precursor Protein: A Novel Excitoprotective Mechanism Involving Modulation of Tau Phosphorylation

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

Oxidation of Cholesterol by Amyloid Precursor Protein and β-Amyloid Peptide

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