Oxidative stress promotes JNK-dependent amyloidogenic processing of normally expressed human APP by differential modification of α-, β- and γ-secretase expression

Quiroz-Báez, Ricardo; Rojas, Emilio; Arias, Clorinda

doi:10.1016/j.neuint.2009.06.012

Cited by 86 publications

(62 citation statements)

References 59 publications

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“…The ratio of the phosphorylated protein level to the total protein level was used to reflect the activation of the proteins. Studies in vitro found that processing of APP, favoring Aβ generation, was JNK-dependent [21], and a JNK inhibitor could reduce Aβ oligomer levels [22]. Furthermore, activation of JNK was associated with Aβ deposition in an AD mice model [23].…”

Section: Discussionmentioning

confidence: 99%

Enhancement of β-amyloid oligomer accumulation after intracerebroventricular injection of streptozotocin, which involves central insulin signaling in a transgenic mouse model

2014

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The β-amyloid (Aβ) oligomer rather than fibrillar Aβ has become the important focus of recent studies on the pathogenesis of Alzheimer's disease (AD). Insulin signaling plays important roles in cognitive disease, such as AD. However, in-vivo evidence for the link between central insulin signaling and the Aβ oligomer are lacking, and the mechanisms underlying the effect of central insulin signaling on AD are still elusive. Our team has established the Presenilin-1 Val97Leu mutant transgenic (PS1V97L) AD mouse model with the intraneuronal Aβ oligomer as the potential initiator for other pathologies, but without extracellular amyloid plaque formation. Using this model, we investigated the roles of disturbed central insulin signaling induced by intracerebroventricular injection of streptozotocin (STZ) in the progression of AD. We observed that PS1V97L mice after intracerebroventricular injection of STZ showed increased Aβ oligomer accumulation and aggravated spatial learning and memory deficit in the absence of diabetes symptoms. Furthermore, STZ administration inhibited the activation of the insulin receptor and enhanced the activation of c-Jun NH2-terminal kinase, which was accompanied by increased production of carboxy-terminal fragments from the amyloid precursor protein, in the brain of PS1V97L mice. Overall, our study provided in-vivo evidence for a role of central insulin signaling in AD progression.

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Section: Discussionmentioning

confidence: 99%

Enhancement of β-amyloid oligomer accumulation after intracerebroventricular injection of streptozotocin, which involves central insulin signaling in a transgenic mouse model

2014

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“…88,90 Oxidative stress has also been found to contribute to amyloid production by changing the balance in expression of the three secretase types. 500 The mechanism of this regulation could involve MT and HIF, because both MT-1 501 and MT-3 502 are induced by HIF and the normal, MTpromoting metal-responsive transcription factor-1 (MTF-1). 503 Hypoxia also reduces the uptake and transport of glutamate in astrocytes, which could further facilitate excitotoxicity.…”

Section: Links Between Oxidative Stress and Other Pathogenic Eventsmentioning

confidence: 99%

Bioinorganic Chemistry of Alzheimer’s Disease

2012

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“…First, increased BACE protein levels and activity in postmortem AD brain [54,162] are linked to increased γ-secretase cleavage of AβPP [163] and correlate with oxidative stress levels [164]. Endogenously and exogenously-induced ROS overproduction increases both BACE1 and PS1 expression and activity [165][166][167][168], which are mediated through the activation of the JNK pathway [169][170][171] and results in increased Aβ production [161,172]. In addition, Jo and colleagues report γ-secretase is responsible for ROS-induced increases in β-secretase activity, since pharmacological or genetic loss of γ-secretase function ameliorates an increase in β-secretase [173].…”

Section: Secretase Enzyme and Mitochondrial Dysfunctionmentioning

confidence: 99%

The Mitochondrial Secret(ase) of Alzheimer's Disease

Young

Bennett

2010

JAD

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Abstract. Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory and cognition and pathologically by extracellular amyloid-β (Aβ) deposits and intraneuronal aggregates of hyperphosphorylated tau. Since its proposal in 1992, the amyloid cascade hypothesis implicates Aβ overproduction as a causative event in disease pathogenesis, and this thinking has predominated the field's understanding of AD pathogenesis and the development of potential therapeutics (i.e., Aβ-reducing agents). Though Aβ has been shown to induce AD pathology, unanswered questions for sporadic AD development suggests this hypothesis is best applied to familial disease only. The more recent mitochondrial cascade hypothesis is supported by data showing that early impairments of mitochondrial dysfunction and oxidative stress may precede Aβ overproduction and deposition. However, the development of Aβ-reducing agents continues. Unfortunately, these agents have not been efficiently tested for their effect on one of the earliest AD pathologies, i.e., mitochondrial dysfunction. This paper will review supporting data for the amyloid and mitochondrial cascade hypotheses, reports of the effects of secretase inhibitors on AD-phenotypic cells and animals, and begin to look at a potential role for γ-secretase, which is localized to mitochondria, in AD-related mitochondrial dysfunction.

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Oxidative stress promotes JNK-dependent amyloidogenic processing of normally expressed human APP by differential modification of α-, β- and γ-secretase expression

Cited by 86 publications

References 59 publications

Enhancement of β-amyloid oligomer accumulation after intracerebroventricular injection of streptozotocin, which involves central insulin signaling in a transgenic mouse model

Enhancement of β-amyloid oligomer accumulation after intracerebroventricular injection of streptozotocin, which involves central insulin signaling in a transgenic mouse model

Bioinorganic Chemistry of Alzheimer’s Disease

The Mitochondrial Secret(ase) of Alzheimer's Disease

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