Causative and susceptibility genes for Alzheimer’s disease: a review

Rocchi, Anna; Pellegrini, Silvia; Siciliano, Gabriele; Murri, Luigi

doi:10.1016/s0361-9230(03)00067-4

Cited by 261 publications

(193 citation statements)

References 280 publications

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“…It was demonstrated in N2a cells that the production of Aβ 1-40 was much higher than that of Aβ , which was beyond the sensitivity of the method to be detected in N2a/ Wt and N2a/vector. In accordance with previous studies that Swedish mutant APP could enhance the production of Aβ [1], more Aβ 1-40 and Aβ were detected in N2a/ APPswe cells. However, the expression of APP in was found to be comparable to that in N2a/APP695 cells.…”

Section: Discussionsupporting

confidence: 93%

“…Among 10 identified isoforms of APP, APP695, which is composed of 695 amino acid residues, was mainly expressed in human brain. Genetic evidence [1] and the characterization of neurotoxicity of Aβ lead to numerous studies on the cell biology of APP and formation of Aβ [2]. However, the functions of APP and Aβ still remain poorly understood until now.…”

Section: Introductionmentioning

confidence: 99%

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Effect of amyloid peptides on serum withdrawal-induced cell differentiation and cell viability

Wang

Zhang

et al. 2004

Cell Res

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Abnormal deposition of amyloid-β(Aβ) peptides and formation of neuritic plaques are recognized as pathological processes in Alzheimer's disease (AD) brain. By using amyloid precursor protein (APP) transfected cells, this study aims to investigate the effect of overproduction of Aβ on cell differentiation and cell viability. It was shown that after serum withdrawal, untransfected cell (N2a/Wt) and vector transfected cells (N2a/vector) extended long and branched cell processes, whereas no neurites was induced in wild type APP (N2a/APP695) and Swedish mutant APP (N2a/ APPswe) transfected N2a cells. After differentiation by serum withdrawal, the localization of APP/Aβ and neurofilament was extended to neurites, whereas those of APP-transfected cells were still restricted within the cell body. Levels of both APP and Aβ were significantly higher in N2a/APP695 and N2a/APPswe than in N2a/Wt, as determined by Western blot and Sandwich ELISA, respectively. To further investigate the effect of Aβ on the inhibition of cell differentiation, we added exogenously the similar level or about 10-times of the Aβ level produced by N2a/APP695 and N2a/APPswe to the culture medium and co-cultured with N2a/Wt for 12 h, and we found that the inhibition of serum withdrawalinduced differentiation observed in N2a/APP695 and N2a/APPswe could not be reproduced by exogenous administration of Aβ into N2a/Wt. We also observed that neither endogenous production nor exogenous addition of Aβ 1-40 or Aβ 1-42 , even to hundreds fold of the physiological concentration, affected obviously the cell viability. These results suggest that the overproduction of Aβ could not arrest cell differentiation induced by serum deprivation and that, at least to a certain degree and in a limited time period, is not toxic to cell viability.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Effect of amyloid peptides on serum withdrawal-induced cell differentiation and cell viability

Wang

Zhang

et al. 2004

Cell Res

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“…Our demonstration that DKK1 is upregulated in the AD brain strengthens the hypothesis that an impairment of the Wnt pathway contributes to the pathophysiology of AD (De Ferrari and Inestrosa, 2000;Garrido et al, 2002;Inestrosa et al, 2002;Caricasole et al, 2003;De Ferrari et al, 2003). It is particularly interesting that the DKK1 receptor LRP5 is also one of the putative receptors for apolipoprotein E (ApoE), and that the genotype ⑀4/⑀4 is an established risk factor for late onset AD (Saunders et al, 2000;Rocchi et al, 2003). Whether ApoE4 binds with high affinity to LRP5 and mimics the action of DKK1 on the Wnt pathway is worthy of investigation.…”

Section: Discussionsupporting

confidence: 75%

Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Associated with Neuronal Degeneration in Alzheimer's Brain

Caricasole¹,

Copani²,

Caraci³

et al. 2004

J. Neurosci.

344

334

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We used primary cultures of cortical neurons to examine the relationship between ␤-amyloid toxicity and hyperphosphorylation of the tau protein, the biochemical substrate for neurofibrillary tangles of Alzheimer's brain. Exposure of the cultures to ␤-amyloid peptide (␤AP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). DKK1 negatively modulates the canonical Wnt signaling pathway, thus activating the tau-phosphorylating enzyme glycogen synthase kinase-3␤. DKK1 was induced at late times after ␤AP exposure, and its expression was dependent on the tumor suppressing protein p53. The antisense induced knock-down of DKK1 attenuated neuronal apoptosis but nearly abolished the increase in tau phosphorylation in ␤AP-treated neurons. DKK1 was also expressed by degenerating neurons in the brain from Alzheimer's patients, where it colocalized with neurofibrillary tangles and distrophic neurites. We conclude that induction of DKK1 contributes to the pathological cascade triggered by ␤-amyloid and is critically involved in the process of tau phosphorylation.

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“…The importance of AAO in the definition of the AD phenotype is well established 12,13 and we demonstrate here the potential utility of the SA method as a proof of principle. Individuals were added in increasing order of AAO.…”

Section: Methodsmentioning

confidence: 62%

Use of phenotypic covariates in association analysis by sequential addition of cases

2006

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Optimal use of phenotype information is important in complex disease gene mapping. We describe a method, sequential addition, for the analysis of case-control data by taking into account of a quantitative trait that is measured in cases but not in controls. The method also provides an estimate of the best phenotype definition for future studies. We demonstrate proof of principle, using an example of incorporation of age-at-onset data into a study of a small sample for association between APOE and late-onset Alzheimer's disease. The sequential addition method finds evidence of association when conventional case -control methods fail. We also illustrate the use of the method for taking account of a dimensional measure of psychosis in a study of the schizophrenia susceptibility gene, dysbindin, in bipolar disorder.

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Causative and susceptibility genes for Alzheimer’s disease: a review

Cited by 261 publications

References 280 publications

Effect of amyloid peptides on serum withdrawal-induced cell differentiation and cell viability

Effect of amyloid peptides on serum withdrawal-induced cell differentiation and cell viability

Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Associated with Neuronal Degeneration in Alzheimer's Brain

Use of phenotypic covariates in association analysis by sequential addition of cases

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