Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer's disease

Guo, Chuangxin; Wang, Tao; Zheng, Wei; Shan, Zhongyan; Teng, Weiping; Wang, Zhan-You

doi:10.1016/j.neurobiolaging.2012.05.009

Cited by 160 publications

(129 citation statements)

References 71 publications

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“…The lack of a change in plaques is consistent with the results in Hanson et al [8]. The mechanism of how the amyloid was affected by DFO is unknown, but was suggested to reduce expression and phosphorylation of APP in Guo et al [25]. Another option is the decrease in protein oxidation, which has been suggested to play an important role in AD [26].…”

Section: Discussionsupporting

confidence: 82%

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Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation

Fine

Renner

Forsberg

et al. 2015

Neuroscience Letters

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Section: Discussionsupporting

confidence: 82%

“…An effect of IN DFO on the amyloid cascade in an amyloid model was also seen by Guo et al [25], which is encouraging, though the sample sizes in that study were small. The lack of a change in plaques is consistent with the results in Hanson et al [8].…”

Section: Discussionsupporting

confidence: 75%

Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation

Fine

Renner

Forsberg

et al. 2015

Neuroscience Letters

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“…8), which is also pathology of AD [28,39]. Lowering brain iron has been shown to reduce memory deficits and neuronal loss in AD animal models and in a clinical trial [11,14,[40][41][42][43]. We recently reported that elevated brain iron, as reflected by elevated cerebrospinal fluid ferritin levels, is associated with accelerated cognitive decline [44], highlighting the role of iron in AD progression.…”

Section: Discussionmentioning

confidence: 99%

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

Lei

Tuo

et al. 2015

Neurotherapeutics

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The amyloid cascade hypothesis of Alzheimer's disease (AD) positions tau protein as a downstream mediator of β-amyloid (Aβ) toxicity This is largely based on genetic cross breeding, which showed that tau ablation in young (3-7-month-old) transgenic mice overexpressing mutant amyloid precursor protein (APP) abolished the phenotype of the APP AD model. This evidence is complicated by the uncertain impact of overexpressing mutant APP, rather than Aβ alone, and for potential interactions between tau and overexpressed APP. Cortical iron elevation is also implicated in AD, and tau promotes iron export by trafficking APP to the neuronal surface. Here, we utilized an alternative model of Aβ toxicity by directly injecting Aβ oligomers into the hippocampus of young and old wild-type and tau knockout mice. We found that ablation of tau protected against Aβ-induced cognitive impairment, hippocampal neuron loss, and iron accumulation. Despite injected human Aβ being eliminated after 5 weeks, enduring changes, including increased APP levels, tau reduction, tau phosphorylation, and iron accumulation, were observed. While the results from our study support the amyloid cascade hypothesis, they also suggest that downstream effectors of Aβ, which propagate toxicity after Aβ has been cleared, may be tractable therapeutic targets.

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“…Due to its half life of 12 min, patients on DFO therapy should undergo subcutaneous infusions from 8-12 h approximately 7 times a week (351,430,437). A recent study, however, highlights the possibility of intranasal DFO administration, which may improve patient compliance (181). Deferiprone and deferasirox are two drugs with iron-chelation activity that are designed to overcome the hydrophilic and poor BBB penetration of DFO.…”

Section: Therapeutic Optionsmentioning

confidence: 99%

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

Singh

Haldar

Tripathi

et al. 2014

Antioxidants & Redox Signaling

177

165

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Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), sporadic Creutzfeldt-Jakob disease (sCJD), and others. In some cases, the underlying cause of iron mis-metabolism is known, while in others, our understanding is, at best, incomplete. Recent evidence implicating key proteins involved in the pathogenesis of AD, PD, and sCJD in cellular iron metabolism suggests that imbalance of brain iron homeostasis associated with these disorders is a direct consequence of disease pathogenesis. A complete understanding of the molecular events leading to this phenotype is lacking partly because of the complex regulation of iron homeostasis within the brain. Since systemic organs and the brain share several iron regulatory mechanisms and iron-modulating proteins, dysfunction of a specific pathway or selective absence of iron-modulating protein(s) in systemic organs has provided important insights into the maintenance of iron homeostasis within the brain. Here, we review recent information on the regulation of iron uptake and utilization in systemic organs and within the complex environment of the brain, with particular emphasis on the underlying mechanisms leading to brain iron mismetabolism in specific neurodegenerative conditions. Mouse models that have been instrumental in understanding systemic and brain disorders associated with iron mis-metabolism are also described, followed by current therapeutic strategies which are aimed at restoring brain iron homeostasis in different neurodegenerative conditions. We conclude by highlighting important gaps in our understanding of brain iron metabolism and mis-metabolism, particularly in the context of neurodegenerative disorders. Antioxid. Redox Signal. 20, 1324Signal. 20, -1363

show abstract

Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer's disease

Cited by 160 publications

References 71 publications

Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation

Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

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