Quantitative neuronal c-Fos and c-Jun expression in Alzheimer’s disease

Marcus, David L.; Strafaci, James A.; Miller, D. C.; Masiá, Susana; Thomas, C.G; Rosman, Jonathan; Hussain, Salman; Freedman, Michael L.

doi:10.1016/s0197-4580(98)00077-3

Cited by 94 publications

(55 citation statements)

References 22 publications

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“…Multiple genes of this group have been previously associated with AD, neurodegenerative diseases, or cognitive performance. Increased immunoreactivity for Fos-related proteins in Alzheimer's disease has been observed in multiple studies (Zhang et al, 1992;Anderson et al, 1994;Marcus et al, 1998), and activation of c-Fos contributes to amyloid ␤-peptide-induced neurotoxicity (Gillardon et al, 1996). In addition to Fos and Arc, several other genes we found have been implicated in the pathophysiology of AD and/or cognitive processes.…”

Section: The Critical Ps1-dependent Transcript Networksupporting

confidence: 69%

Presenilin-1-Dependent Transcriptome Changes

et al. 2005

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Familial forms of Alzheimer's disease (FADs) are caused by the expression of mutant presenilin 1 (PS1) or presenilin 2. Using DNA microarrays, we explored the brain transcription profiles of mice with conditional knock-out of PS1 (cKO PS1) in the forebrain. In parallel, we performed a transcription profiling of the hippocampus and frontal cortex of the FAD-linked ⌬E9 mutant transgenic (TG) mice and matched controls [TG mice expressing wild-type human PS1 (hPS1)]. When the TG and cKO datasets were cross-compared, the majority of the 30 common expression alterations were in opposite direction, suggesting that the FAD-linked PS1 variant produces transcriptome changes primarily by gain of aberrant function. Our microarray studies also revealed an unanticipated inverse correlation of transcript levels between the brains of mice that coexpress ⌬E9 hPS1ϩ amyloid precursor protein (APP) 695 Swe and ⌬E9 hPS1 single transgenic mice. The opposite directionality of these changes in transcript levels must be a function of APP and/or APP derivatives.

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Section: The Critical Ps1-dependent Transcript Networksupporting

confidence: 69%

Presenilin-1-Dependent Transcriptome Changes

et al. 2005

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“…For example both JNK and GSK-3 are implicated in Alzheimer's disease. Cortical neurons lacking JNK3 or cells expressing dominant-negative c-Jun are protected from amyloid-␤ peptide (a key player in Alzheimer's pathology)-induced death (39), and elevated JNK activity and c-Jun protein levels were detected in Alzheimer's disease brains (37,48,61). Similarly, GSK-3 activity is elevated in the brain in Alzheimer's patients, and in cultured hippocampal neurons GSK-3 activity is induced by amyloid-␤ peptide (43,50).…”

Section: Discussionmentioning

confidence: 99%

Lithium Blocks the c-Jun Stress Response and Protects Neurons via Its Action on Glycogen Synthase Kinase 3

Hongisto

Smeds

Brecht

et al. 2003

Molecular and Cellular Biology

131

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Lithium has been used as an effective mood-stabilizing drug for the treatment of manic episodes and depression for 50 years. More recently, lithium has been found to protect neurons from death induced by a wide array of neurotoxic insults. However, the molecular basis for the prophylactic effects of lithium have remained obscure. A target of lithium, glycogen synthase kinase 3 (GSK-3), is implicated in neuronal death after trophic deprivation. The mechanism whereby GSK-3 exerts its neurotoxic effects is also unknown. Here we show that lithium blocks the canonical c-Jun apoptotic pathway in cerebellar granule neurons deprived of trophic support. This effect is mimicked by the structurally independent inhibitors of GSK-3, FRAT1, and indirubin. Like lithium, these prevent the stress induced c-Jun protein increase and subsequent apoptosis. These events are downstream of c-Jun transactivation, since GSK-3 inhibitors block neuronal death induced by constitutively active c-Jun (Ser/Thr3Asp) and FRAT1 expression inhibits AP1 reporter activity. Consistent with this, AP1-dependent expression of proapoptotic Bim requires GSK-3-like activity. These data suggest that a GSK-3-like kinase acts in tandem with c-Jun N-terminal kinase to coordinate the full execution of the c-Jun stress response and neuronal death in response to trophic deprivation.

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“…In this respect, it is interesting to note that a relationship between 5-LOX promoter polymorphism and AD onset was recently reported. 55 One of the typical feature found in post-mortem studies on brains from AD patients is an overexpression of c-Jun, 56 which is also a hallmark of Ab-induced apoptosis in neuronal cultures. 17,44 This transcription factor was found to play a major role in Ab-induced neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

et al. 2004

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The cyclo-oxygenase (COX) and lipoxygenase (LOX) pathways belong to the eicosanoid synthesis pathway, a major component of the chronic inflammatory process occurring in Alzheimer's disease (AD). Clinical studies reported beneficial effects of COX inhibitors, but little is known about the involvement of LOXs in AD pathogenesis. b-amyloid peptide (Ab) accumulation contributes to neurodegeneration in AD, but mechanisms underlying Ab toxicity have not been fully elucidated yet. Here, using an antisense oligonucleotide-based strategy, we show that blockade of 12-LOX expression prevents both Ab-induced apoptosis and overexpression of c-Jun, a factor required for the apoptotic process, in cortical neurons. Conversely, the 12-LOX metabolite, 12(S)-HETE (12(S)-hydroxy-(5Z, 8Z, 10E, 14Z)-eicosatetraenoic acid), promoted c-Jun-dependent apoptosis. Specificity of the 12-LOX involvement was further supported by the observed lack of contribution of 5-LOX in this process. These data indicate that blockade of 12-LOX expression disrupts a c-Jun-dependent apoptosis pathway, and suggest that 12-LOX may represent a new target for the treatment of AD.

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Quantitative neuronal c-Fos and c-Jun expression in Alzheimer’s disease

Cited by 94 publications

References 22 publications

Presenilin-1-Dependent Transcriptome Changes

Presenilin-1-Dependent Transcriptome Changes

Lithium Blocks the c-Jun Stress Response and Protects Neurons via Its Action on Glycogen Synthase Kinase 3

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

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