A role for amyloid precursor protein translation to restore iron homeostasis and ameliorate lead (Pb) neurotoxicity

Rogers, Jack T.; Venkataramani, Vivek; Washburn, Cecilia; Liu, Yanyan; Tummala, Vinusha; Jiang, Hong; Smith, Ann; Cahill, Catherine M.

doi:10.1111/jnc.13671

Cited by 39 publications

(32 citation statements)

References 101 publications

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“…Therefore, maintaining iron homeostasis can inhibit APP translation and Aβ overproduction by activating α-secretase [39]. On the other hand, it was reported that iron could promote APP translation to attenuate the toxicities of lead (Pb) [40], suggesting a protective role of iron in APP metabolism. In addition to the effects of iron on APP as mentioned above, APP could reversely affect iron, i.e., to stabilize the iron exporter FPN1, and the heavy subunit of the iron-storage protein, ferritin; by which the elevated APP can regulate metabolisms of brain and peripheral iron to attenuate brain iron elevation during aging [41].…”

Section: Ironmentioning

confidence: 99%

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

298

188

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Background: The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance of these metal ions in the brain is closely related to the onset and progression of Alzheimer's disease (AD), the most common neurodegenerative disorder in the elderly. Main body: Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress. The metal ions imbalance and oxidative stress together or independently promote amyloid-β (Aβ) overproduction by activating βor γ-secretases and inhibiting α-secretase, it also causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase-5 (CDK5), mitogenactivated protein kinases (MAPKs), etc., and inhibiting protein phosphatase 2A (PP2A). The metal ions imbalances can also directly or indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial and autophagic dysfunctions, which can cause or aggravate Aβ and tau aggregation/accumulation, and impair synaptic functions. Even worse, the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition. The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits, such as seen in AD patients. Conclusion: The metal ions imbalance induces Aβ and tau pathologies by directly or indirectly affecting multiple cellular/ subcellular pathways, and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/ deposition. Therefore, adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies, which provides new research directions for AD treatment.

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Section: Ironmentioning

confidence: 99%

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

298

188

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“…Stably expressing cell lines overexpressing human wild-type APP695 isoform (SH-SY5Y APP 695 ) or the empty vector (pCEP4) were previously established (Venkataramani et al 2010). The stable SH-SY5Y cell line transfected with the APP 5 0 -UTR luciferase or HIRE_CAT constructs were described previously (Thomson et al 2005;Rogers et al 2016).…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

“…: E1500, Promega, Madison, WI, USA) was used according to manufacturer's directions to measure the luciferase activity. Reporter assays for balanced luciferase assays using the transfectants encoding the APP 5 0 -UTR luciferase (luc) reporter construct pGAL were as described previously (Rogers et al 2016). The activity of the Ferritin-H chain specific iron-responsive element (H-Ferritin IRE) was assessed using the plasmid construct, designated as HIRE_CAT, in which the H-Ferritin IRE had been ligated in front of a chloramphenicol acetyltransferase (CAT) reporter gene.…”

Section: Quantification Of Luciferase (Luc) and Chloramphenicol Acetymentioning

confidence: 99%

“…We previously reported that the xenobiotic metal lead caused a translational repression of APP and H-Ferritin in SH-SY5Y cells (Rogers et al 2016). Based on this, we evaluated Mndose responsive effects in the range of 10-100 lmol and analyzed protein expression of the iron homeostatic gene products APP and H-Ferritin.…”

Section: Manganese Acutely Reduces Protein Levels Of Neuroprotective mentioning

confidence: 99%

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Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H‐Ferritin

Venkataramani

Doeppner

Willkommen

et al. 2018

Journal of Neurochemistry

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For more than 150 years, it is known that occupational overexposure of manganese (Mn) causes movement disorders resembling Parkinson's disease (PD) and PD-like syndromes. However, the mechanisms of Mn toxicity are still poorly understood. Here, we demonstrate that Mn dose- and time-dependently blocks the protein translation of amyloid precursor protein (APP) and heavy-chain Ferritin (H-Ferritin), both iron homeostatic proteins with neuroprotective features. APP and H-Ferritin are post-transcriptionally regulated by iron responsive proteins, which bind to homologous iron responsive elements (IREs) located in the 5'-untranslated regions (5'-UTRs) within their mRNA transcripts. Using reporter assays, we demonstrate that Mn exposure repressed the 5'-UTR-activity of APP and H-Ferritin, presumably via increased iron responsive proteins-iron responsive elements binding, ultimately blocking their protein translation. Using two specific Fe -specific probes (RhoNox-1 and IP-1) and ion chromatography inductively coupled plasma mass spectrometry (IC-ICP-MS), we show that loss of the protective axis of APP and H-Ferritin resulted in unchecked accumulation of redox-active ferrous iron (Fe ) fueling neurotoxic oxidative stress. Enforced APP expression partially attenuated Mn-induced generation of cellular and lipid reactive oxygen species and neurotoxicity. Lastly, we could validate the Mn-mediated suppression of APP and H-Ferritin in two rodent in vivo models (C57BL6/N mice and RjHan:SD rats) mimicking acute and chronic Mn exposure. Together, these results suggest that Mn-induced neurotoxicity is partly attributable to the translational inhibition of APP and H-Ferritin resulting in impaired iron metabolism and exacerbated neurotoxic oxidative stress. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/.

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“…However, these studies were focused on the change of ion or trace elements concentration after lead exposure resulting in disturbance of brain function through an unclear pathway. Because lead is a divalent metal carries electronegativity and particle radius similarities with other ion or trace elements in the body [15,16], and its absorption, distribution could mimic other divalent trace elements such as iron, zinc, calcium etc. There is no available data to demonstrate the signi cant changes of divalent metal ion or trace elements in the brain after lead exposure.…”

Section: Introductionmentioning

confidence: 99%

Lead Exposure Induced Copper Clearance Disorder of Blood-CSF Barrier

Wang

et al. 2020

Preprint

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Lead is a heavy metal commonly found in the environment with known neurotoxicity, hematological and other toxicities. It has been found that lead exposure can disturb partial metal regulatory function in the blood-CSF barrier (BCB). Copper, which play an important role in maintaining normal brain function, can accumulate in brain after lead exposure. The studies of Alzheimer's disease (AD) indicated that abnormal copper homeostasis in cerebrospinal fluid (CSF) may be involved in the pathogenesis. However, the mechanism of copper disturbance in the brain caused by lead is still unknown. This study was designed to investigate copper clearance by the BCB in central nervous system after lead exposure, with focus on copper transporter protein CTR1/ATP7A. Inductively coupled plasma mass spectrometry (ICP-MS) and principal component analysis (PCA) were used to identify the changes of heavy metal level in hippocampus and CSF after lead exposure. It was found that the change in copper level was most pronounced in the brain between 3 to 12 weeks post lead exposure. Ventriculo-cisternal (VC) perfusion in Sprague Dawley (SD) rat suggested that the ability of BCB to deliver copper from the CSF to blood was decreased after lead exposure. Confocal microscope showed evidence of the presence of excess copper in the choroid plexus cells leading to CTR1/ATP7A shifting toward the apical microvilli facing the CSF after lead exposure. Finally, transmission electron microscopy (TEM) was used for observation of the microstructure of choroid plexus showed altered mitochondrial morphology with decreased microvilli after lead exposure. Our data suggested that lead exposure may alter BCB cellular microscopic structure and its copper transport, clearance function that might further cause brain injury.

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A role for amyloid precursor protein translation to restore iron homeostasis and ameliorate lead (Pb) neurotoxicity

Cited by 39 publications

References 101 publications

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H‐Ferritin

Lead Exposure Induced Copper Clearance Disorder of Blood-CSF Barrier

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