Signal transduction during amyloid-β-peptide neurotoxicity: role in Alzheimer disease

Fuentealba, Rodrigo A.; Farı́as, Ginny G.; Scheu, Jessica; Bronfman, Miguel; Marzolo, Marı́a Paz; Inestrosa, Nibaldo C.

doi:10.1016/j.brainresrev.2004.07.018

Cited by 125 publications

(93 citation statements)

References 156 publications

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“…This approach revealed that genes affected by disease but not gender were involved several cellular processes such as transmission of nerve impulse, synaptic transmission, cell-cell signaling, establishment of localization, localization, transport (Fig 3). Among the genes that exhibit gender-independent altered expression in PD are: neuronal beta-catenin, which has been implicated in Alzheimer disease and synaptic plasticity (Fuentealba et al, 2004;Goda, 2002); PAEL-R, a protein accumulated in Lewy bodies (Murakami et al, 2004) and a potential parkin substrate (Nakahara et al, 2003;Yang et al, 2003); kallikrein 6, involved in ASYN degradation (Iwata et al, 2003); and transferrin, which may be related to iron deposition observed in PD brain (Morris et al, 1994).…”

Section: Microarray Resultsmentioning

confidence: 99%

Effects of gender on nigral gene expression and parkinson disease

Cantuti-Castelvetri

Keller-McGandy

Bouzou

et al. 2007

Neurobiology of Disease

214

212

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To identify gene expression patterns in human dopamine (DA) neurons in the substantia nigra pars compacta (SNc) of male and female control and Parkinson disease (PD) patients, we harvested DA neurons from frozen SNc from 16 subjects (4 male PD, 4 female PD, 4 male and 4 female controls) using Laser Capture microcrodissection and microarrays. We assessed for enrichment of functional categories with a hypergeometric distribution. The data were validated with QPCR.We observed that gender has a pervasive effect on gene expression in DA neurons. Genes upregulated in females relative to males are mainly involved in signal transduction and neuronal maturation, while in males some of the upregulated genes (alpha-synuclein and PINK1) were previously implicated in the pathogenesis of PD. In females with PD we found alterations in genes with protein kinase activity, genes involved in proteolysis and WNT signaling pathway, while in males with PD there were alterations in protein-binding proteins and copper-binding proteins.Our data reveal broad gender-based differences in gene expression in human dopaminergic neurons of SNc that may underlie the predisposition of males to PD. Moreover, we show that gender influences the response to PD, suggesting that the nature of the disease and the response to treatment may be gender-dependent.

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Section: Microarray Resultsmentioning

confidence: 99%

Effects of gender on nigral gene expression and parkinson disease

Cantuti-Castelvetri

Keller-McGandy

Bouzou

et al. 2007

Neurobiology of Disease

214

212

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“…Therefore, β-catenin degradation after stroke may down-regulate pro-survival gene expression activated by β-catenin and dismantle cell-cell adhesion and connection, thus aggravating ischemic injury. Indeed, β-catenin degradation has been shown to increase while its overexpression blocks apoptosis in vitro [7], and protein levels of β-catenin decrease in patient brains with Alzheimer's disease [4] [5]. β-catenin degradation may also play critical roles in pathological processes after stroke.…”

Section: Discussionmentioning

confidence: 99%

“…Stabilized β-catenin translocates into the nuclei, activating gene expression that supports cell survival [9,11]. β-catenin has been shown to decrease in brains of patients with Alzheimer's disease [5]. In addition, β-catenin knockdown results in apoptosis, whereas β-catenin overexpression prevents neuronal death in vitro [7].…”

Section: Introductionmentioning

confidence: 99%

Hypothermia blocks β-catenin degradation after focal ischemia in rats

Zhang¹,

Ren²,

Gao³

et al. 2008

Brain Research

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Dephosphorylated and activated glycogen synthase kinase (GSK) 3β hyperphophorylates β-catenin, leading to its ubiquitin-proteosome-mediated degradation. β-catenin-knockdown increases while β-catenin overexpression prevents neuronal death in vitro; in addition, protein levels of β-catenin are reduced in the brain of Alzheimer's patients. However, whether β-catenin degradation is involved in stroke-induced brain injury is unknown. Here we studied activities of GSK3 β and β-catenin, and the protective effect of moderate hypothermia (30 °C) on these activities after focal ischemia in rats. The results of Western blot showed that GSK3 β was dephosphorylated at 5 and 24 hours after stroke in the normothermic (37 °C) brain; hypothermia augmented GSK3β dephosphorylation. Because hypothermia reduces infarction, these results contradict with previous studies showing that GSK3β dephosphorylation worsens neuronal death. Nevertheless, hypothermia blocked degradation of total GSK3β protein. Corresponding to GSK3β activity in normothermic rats, β-catenin phosphorylation transiently increased at 5 hours in both the ischemic penumbra and core, and the total protein level of β-catenin degraded after normothermic stroke. Hypothermia did not inhibit β-catenin phosphorylation, but it blocked β-catenin degradation in the ischemic penumbra. In conclusion, moderate hypothermia can stabilize β-catenin, which may contribute to the protective effect of moderate hypothermia.

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“…Not only is GSK3 intimately involved in many aspects of amyloid precursor protein metabolism and Aβ production, but GSK3 also contributes to Aβ-induced neuronal toxicity. Aβ is well-known to cause neuronal death when applied to cultured cells or to brain in vivo, and inhibition of GSK3 by a variety of methods significantly attenuates the neurotoxicity caused by Aβ [79][80][81][82][83][84][85]]. This appears not to be a "bystander" effect of GSK3 because treatment with Aβ activates GSK3 in a number of conditions, indicating a direct link between Aβ-induced GSK3 activation and neurotoxicity [79,86,87].…”

Section: Neurodegenerative Diseases: Gsk3 and Admentioning

confidence: 98%

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

2006

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Deciphering what governs inflammation and its effects on tissues is vital for understanding many pathologies. The recent discovery that glycogen synthase kinase-3 (GSK3) promotes inflammation reveals a new component of its well-documented actions in several prevalent diseases which involve inflammation, including mood disorders, Alzheimer's disease, diabetes, and cancer. Involvement in such disparate conditions stems from the widespread influences of GSK3 on many cellular functions, with this review focusing on its regulation of inflammatory processes. GSK3 promotes the production of inflammatory molecules and cell migration, which together make GSK3 a powerful regulator of inflammation, while GSK3 inhibition provides protection from inflammatory conditions in animal models. The involvement of GSK3 and inflammation in these diseases are highlighted. Thus, GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions.

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Signal transduction during amyloid-β-peptide neurotoxicity: role in Alzheimer disease

Cited by 125 publications

References 156 publications

Effects of gender on nigral gene expression and parkinson disease

Effects of gender on nigral gene expression and parkinson disease

Hypothermia blocks β-catenin degradation after focal ischemia in rats

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

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