Zinc Inhibits Amyloid β Production from Alzheimer's Amyloid Precursor Protein in SH-SY5Y Cells

Lee, Jinu; Kim, Chul Hoon; Kim, Dong Goo; Ahn, Young Soo

doi:10.4196/kjpp.2009.13.3.195

Cited by 13 publications

(10 citation statements)

References 33 publications

(19 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was found that APP synthesis is regulated by zinc-containing transcription factors NF- κ B and sp1 (Grilli et al, 1996). Zinc is also involved in processing of APP protein (Lee et al, 2009). The processing of APP relies on a number of activities by enzymes secretases (α-,β-, and γ-).…”

Section: Zinc and Alzheimer's Diseasementioning

confidence: 99%

Zinc homeostasis and neurodegenerative disorders

Szewczyk

2013

Front. Aging Neurosci.

247

149

View full text Add to dashboard Cite

Zinc is an essential trace element, whose importance to the function of the central nervous system (CNS) is increasingly being appreciated. Alterations in zinc dyshomeostasis has been suggested as a key factor in the development of several neuropsychiatric disorders. In the CNS, zinc occurs in two forms: the first being tightly bound to proteins and, secondly, the free, cytoplasmic, or extracellular form found in presynaptic vesicles. Under normal conditions, zinc released from the synaptic vesicles modulates both ionotropic and metabotropic post-synaptic receptors. While under clinical conditions such as traumatic brain injury, stroke or epilepsy, the excess influx of zinc into neurons has been found to result in neurotoxicity and damage to postsynaptic neurons. On the other hand, a growing body of evidence suggests that a deficiency, rather than an excess, of zinc leads to an increased risk for the development of neurological disorders. Indeed, zinc deficiency has been shown to affect neurogenesis and increase neuronal apoptosis, which can lead to learning and memory deficits. Altered zinc homeostasis is also suggested as a risk factor for depression, Alzheimer's disease (AD), aging, and other neurodegenerative disorders. Under normal CNS physiology, homeostatic controls are put in place to avoid the accumulation of excess zinc or its deficiency. This cellular zinc homeostasis results from the actions of a coordinated regulation effected by different proteins involved in the uptake, excretion and intracellular storage/trafficking of zinc. These proteins include membranous transporters (ZnT and Zip) and metallothioneins (MT) which control intracellular zinc levels. Interestingly, alterations in ZnT and MT have been recently reported in both aging and AD. This paper provides an overview of both clinical and experimental evidence that implicates a dysfunction in zinc homeostasis in the pathophysiology of depression, AD, and aging.

show abstract

Section: Zinc and Alzheimer's Diseasementioning

confidence: 99%

Zinc homeostasis and neurodegenerative disorders

Szewczyk

2013

Front. Aging Neurosci.

247

149

View full text Add to dashboard Cite

show abstract

“…Inhibitors of acyl-coenzyme A cholesterol acyl transferase (ACAT) also reduced Aβ production by decreasing the ratio of mature to immature APP [42]. Similarly, zinc [43] and O-glycosylation inhibitors [44], both of which retarded APP maturation, also reduced Aβ generation. Since BCNU did not affect the activities of any of the secretases, reduced Aβ generation most likely results from altered trafficking of APP due to accumulation of immature APP.…”

Section: Discussionmentioning

confidence: 99%

Striking reduction of amyloid plaque burden in an Alzheimer's mouse model after chronic administration of carmustine

Hayes

Dey

Palavicini

et al. 2013

BMC Med

View full text Add to dashboard Cite

BackgroundCurrently available therapies for Alzheimer's disease (AD) do not treat the underlying cause of AD. Anecdotal observations in nursing homes from multiple studies strongly suggest an inverse relationship between cancer and AD. Therefore, we reasoned that oncology drugs may be effective against AD.MethodsWe screened a library of all the FDA-approved oncology drugs and identified bis-chloroethylnitrosourea (BCNU or carmustine) as an effective amyloid beta (Aβ) reducing compound. To quantify Aβ levels, Chinese hamster ovary (CHO) cells stably expressing amyloid precursor protein 751WT (APP751WT) called 7WD10 cells were exposed to different concentrations of BCNU for 48 hours and the conditioned media were collected. To detect Aβ the conditioned media were immunoprecipitated with Ab9 antibody and subjected to immunoblot detection. Amyloid plaques were quantified in the brains of a mouse model of AD after chronic exposure to BCNU by thoflavin S staining.ResultsBCNU decreased normalized levels of Aβ starting from 5 μM by 39% (P < 0.05), 10 μM by 51% (P < 0.01) and 20 μM by 63% (P < 0.01) in CHO cells compared to a control group treated with butyl amine, a structural derivative of BCNU. Interestingly, soluble amyloid precursor protein α (sAPPα) levels were increased to 167% (P < 0.01) at 0.5 μM, 186% (P < 0.05) at 1 μM, 204% (P < 0.01) at 5 μM and 152% (P < 0.05) at 10 μM compared to untreated cells. We also tested the effects of 12 structural derivatives of BCNU on Aβ levels, but none of them were as potent as BCNU. BCNU treatment at 5 μM led to an accumulation of immature APP at the cell surface resulting in an increased ratio of surface to total APP by 184% for immature APP, but no change in mature APP. It is also remarkable that BCNU reduced Aβ generation independent of secretases which were not altered up to 40 μM. Interestingly, levels of transforming growth factor beta (TGFβ) were increased at 5 μM (43%, P < 0.05), 10 μM (73%, P < 0.01) and 20 μM (92%, P < 0.001). Most significantly, cell culture results were confirmed in vivo after chronic administration of BCNU at 0.5 mg/kg which led to the reduction of Aβ40 by 75% and amyloid plaque burden by 81%. Conversely, the levels of sAPPα were increased by 45%.ConclusionsBCNU reduces Aβ generation and plaque burden at non-toxic concentrations possibly through altered intracellular trafficking and processing of APP. Taken together these data provided unequivocal evidence that BCNU is a potent secretase-sparing anti-Aβ drug.See related commentary article here http://www.biomedcentral.com/1741-7015/11/82

show abstract

“…In various neuronal diseases, such as stroke, epilepsy, mechanical trauma, and Alzheimer's disease, the precise mechanism of cytotoxicity is less known, but emerging evidence suggests that excess Zn 2+ may kill neurons through the inhibition of ATP synthesis [ 98 ]. In contrast to the previously mentioned proapoptotic role of Zn 2+ [ 84 ], Zn 2+ could participate in the inhibition of proapoptotic caspase-3 activation [ 71 ] and in the reduction of amyloid production in experimental neuronal cells [ 99 ], since these effects are lost in response to low levels of Zn 2+ . In zinc deficiency, neural cell apoptosis was associated with an increase in phosphorylation of p53 and its translocation into mitochondria [ 97 ].…”

Section: Zinc and Its Role In Health And Diseasementioning

confidence: 92%

The Critical Roles of Zinc: Beyond Impact on Myocardial Signaling

Lee

Noh

Pronto

et al. 2015

Korean J Physiol Pharmacol

View full text Add to dashboard Cite

Zinc has been considered as a vital constituent of proteins, including enzymes. Mobile reactive zinc (Zn2+) is the key form of zinc involved in signal transductions, which are mainly driven by its binding to proteins or the release of zinc from proteins, possibly via a redox switch. There has been growing evidence of zinc's critical role in cell signaling, due to its flexible coordination geometry and rapid shifts in protein conformation to perform biological reactions. The importance and complexity of Zn2+ activity has been presumed to parallel the degree of calcium's participation in cellular processes. Whole body and cellular Zn2+ levels are largely regulated by metallothioneins (MTs), Zn2+ importers (ZIPs), and Zn2+ transporters (ZnTs). Numerous proteins involved in signaling pathways, mitochondrial metabolism, and ion channels that play a pivotal role in controlling cardiac contractility are common targets of Zn2+. However, these regulatory actions of Zn2+ are not limited to the function of the heart, but also extend to numerous other organ systems, such as the central nervous system, immune system, cardiovascular tissue, and secretory glands, such as the pancreas, prostate, and mammary glands. In this review, the regulation of cellular Zn2+ levels, Zn2+-mediated signal transduction, impacts of Zn2+ on ion channels and mitochondrial metabolism, and finally, the implications of Zn2+ in health and disease development were outlined to help widen the current understanding of the versatile and complex roles of Zn2+.

show abstract

Zinc Inhibits Amyloid β Production from Alzheimer's Amyloid Precursor Protein in SH-SY5Y Cells

Cited by 13 publications

References 33 publications

Zinc homeostasis and neurodegenerative disorders

Zinc homeostasis and neurodegenerative disorders

Striking reduction of amyloid plaque burden in an Alzheimer's mouse model after chronic administration of carmustine

The Critical Roles of Zinc: Beyond Impact on Myocardial Signaling

Contact Info

Product

Resources

About