Iron increases APP translation and amyloid-beta production in the retina

Guo, Lucie Y.; Alekseev, Oleg; Li, Yafeng; Song, Ying; Dunaief, Joshua L.

doi:10.1016/j.exer.2014.10.012

Cited by 30 publications

(23 citation statements)

References 41 publications

(56 reference statements)

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“…The binding of iron to Aβ or to tau induces Aβ aggregation and tau hyperphosphorylation, leading to formation of senile plaques and NFTs, and as well as the increased neurotoxicity of Aβ and tau [32,33]. Iron increases APP translation and Aβ42 production/accumulation in the retina with no observed change in secretase levels or cleavage activities [34]. Fe 2+ ions bound to the N-terminal region of Aβ, which can modify Aβ and generate oxygen radicals to induce damages on the membrane surface [35].…”

Section: Ironmentioning

confidence: 99%

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

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

251

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

251

188

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“…For example, large drusen at the RPE/Bruch’s membrane interface, a hallmark of AMD, typically contain significant levels of aggregated Aβ (Isas et al, 2010; Johnson et al, 2002). Furthermore, known AMD risk factors including high-fat/high cholesterol diet, light damage, exposure to cigarette smoke and iron overload are associated with Aβ build-up (Beatty et al, 2000; Cano et al, 2010; Dasari et al, 2011; Ding et al, 2008, 2011; Dong et al, 2012; Guo et al, 2014; Malek et al, 2005; Organisciak and Vaughan, 2010; Pikuleva and Curcio, 2014; Sharma et al, 2014; Woodell and Rohrer, 2014). In addition, partial rescue/protection from retinal/RPE abnormalities in retinal degeneration mouse models can be achieved by Aβ-directed immunotherapy (Ding et al, 2008, 2011; Guo et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Reduction of amyloid-beta levels in mouse eye tissues by intra-vitreally delivered neprilysin

Parthasarathy

Chow

Derafshi

et al. 2015

Experimental Eye Research

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Amyloid-beta (Aβ) is a group of aggregation-prone, 38- to 43-amino acid peptides generated in the eye and other organs. Numerous studies suggest that the excessive build-up of low-molecular-weight soluble oligomers of Aβ plays a role in the progression of Alzheimer’s disease and other brain degenerative diseases. Recent studies raise the hypothesis that excessive Aβ levels may contribute also to certain retinal degenerative diseases. These findings, together with evidence that a major portion of Aβ is released as monomer into the extracellular space, raise the possibility that a technology enabling the enzymatic break-down of monomeric Aβ in the living eye under physiological conditions could prove useful for research on ocular Aβ physiology and, perhaps ultimately, for therapeutic applications. Neprilysin (NEP), an endopeptidase known to cleave Aβ monomer into inactive products, is a membrane-associated protein. However, sNEP, a recombinant form of the NEP catalytic domain, is soluble in aqueous medium. With the aim of determining the Aβ-cleaving activity of exogenous sNEP in the microenvironment of the intact eye, we analyzed the effect of intra-vitreally delivered sNEP on ocular Aβ levels in mice that exhibit readily measurable, aqueous buffer-extractable Aβ40 and Aβ42, two principal forms of Aβ. Anesthetized 10-month wild-type (C57BL/6J) and 2–3-month 5XFAD transgenic mice received intra-vitreal injections of sNEP (0.004 – 10 μg) in one eye and were sacrificed at defined post-treatment times (30 min – 12 weeks). Eye tissues (combined lens, vitreous, retina, RPE and choroid) were homogenized in phosphate-buffered saline, and analyzed for Aβ40 and Aβ42 (ELISA) and for total protein (Bradford assay). The fellow, untreated eye of each mouse served as control, and concentrations of Aβ (pmol/g protein) in the treated eye were normalized to that of the untreated control eye. In C57BL/6J mice, as measured at 2 hr after sNEP treatment, increasing amounts of injected sNEP yielded progressively greater reductions of Aβ40, ranging from 12% ± 3% (mean ± SEM; n=3) with 4 ng sNEP to 85% ± 13% (n=5) with 10 μg sNEP. At 4 ng sNEP the average Aβ40 reduction reached >70% by 24 hr following treatment and remained near this level for about 8 weeks. In 5XFAD mice, 10 μg sNEP produced an Aβ40 decrease of 99% ± 1% (n=4) and a substantial although smaller decrease in Aβ42 (42% ± 36%; n=4) within 24 hr. Electroretinograms (ERGs) were recorded from eyes of C57BL/6J and 5XFAD mice at 9 days following treatment with 4 ng or 10 μg sNEP, conditions that on average led, respectively, to an 82% and 91% Aβ40 reduction in C57BL/6J eyes, an 87% and 92% Aβ40 reduction in 5XFAD eyes, and a 23% and 52% Aβ42 reduction in 5XFAD eyes. In all cases, sNEP-treated eyes exhibited robust ERG responses, consistent with a general tolerance of the posterior eye tissues to the investigated conditions of sNEP treatment. The sNEP-mediated decrease of ocular Aβ levels reported here represents a possible approach for determining effects of Aβ reduction in normal...

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“…Due to its role in stabilizing microtubules, tau phosphorylation and aggregation interferes with anterograde axonal transport and inhibits mitochondrial transport, resulting in loss of energy and generation of ROS [ 91 ]. Additionally, Aβ deposits sequester redox-active metals such as iron and induce toxicity by iron-catalyzed ROS, which causes additional Aβ generation and aggregation, creating a positive feed-forward loop [ 4 , 5 , 92 , 93 ]. Moreover, Aβ deposits and intracellular NFTs initiate a cascade of events that activate retinal astrocytes and microglia with the secretion of inflammatory cytokines, including interleukin−1β (IL-1β), IL-6, and tumor necrosis factor α (TNFα) [ 94 , 95 ], which, along with Aβ-generated ROS, create a toxic microenvironment leading to RGC death and thinning of the RNFL.…”

Section: Methodsmentioning

confidence: 99%

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

Ashok

Singh

Chaudhary

et al. 2020

IJMS

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Age-related macular degeneration (AMD) and glaucoma are degenerative conditions of the retina and a significant cause of irreversible blindness in developed countries. Alzheimer’s disease (AD), the most common dementia of the elderly, is often associated with AMD and glaucoma. The cardinal features of AD include extracellular accumulation of amyloid β (Aβ) and intracellular deposits of hyper-phosphorylated tau (p-tau). Neuroinflammation and brain iron dyshomeostasis accompany Aβ and p-tau deposits and, together, lead to progressive neuronal death and dementia. The accumulation of Aβ and iron in drusen, the hallmark of AMD, and Aβ and p-tau in retinal ganglion cells (RGC), the main retinal cell type implicated in glaucoma, and accompanying inflammation suggest overlapping pathology. Visual abnormalities are prominent in AD and are believed to develop before cognitive decline. Some are caused by degeneration of the visual cortex, while others are due to RGC loss or AMD-associated retinal degeneration. Here, we review recent information on Aβ, p-tau, chronic inflammation, and iron dyshomeostasis as common pathogenic mechanisms linking the three degenerative conditions, and iron chelation as a common therapeutic option for these disorders. Additionally discussed is the role of prion protein, infamous for prion disorders, in Aβ-mediated toxicity and, paradoxically, in neuroprotection.

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Iron increases APP translation and amyloid-beta production in the retina

Cited by 30 publications

References 41 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

Reduction of amyloid-beta levels in mouse eye tissues by intra-vitreally delivered neprilysin

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

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