The Effects of Enhanced Zinc on Spatial Memory and Plaque Formation in Transgenic Mice

Linkous, David H.; Adlard, Paul A.; Wanschura, Patricia B.; Conko, Kathryn M.; Flinn, Jane M.

doi:10.3233/jad-2009-1162

Cited by 54 publications

(41 citation statements)

References 30 publications

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“…Among many other factors, metal ions (e.g., Al, Cu, Fe, and Zn) have been shown to affect the pathways of Ab folding. The abnormal aggregation of Ab could stimulate astrocyte activation as well as oxidative stress events, which both result in impairment of neuronal functions Behavioral studies on transgenic mice examining the effect of Zn supplementation reported an increased impairment of spatial memory, but with a concomitant unexpected reduction of Ab deposits (Linkous et al 2009). In contrast, compounds affecting Zn homeostasis have been shown to decrease Ab brain deposition (Lee et al 2004;Adlard et al 2008).…”

Section: Zincmentioning

confidence: 97%

Metal Ion Physiopathology in Neurodegenerative Disorders

2009

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Metal dyshomeostasis in the brain (BMD) has often been proposed as a possible cause for several neurodegenerative disorders (NDs). Nevertheless, the precise nature of the biochemical mechanisms of metal involvement in NDs is still largely unknown. Mounting evidence suggests that normal aging itself is characterized by, among other features, a significant degree of metal ion dysmetabolism in the brain. This is probably the result of a progressive deterioration of the metal regulatory systems and, at least in some cases, of life-long metal exposure and brain accumulation. Although alterations of metal metabolism do occur to some extent in normal aging, they appear to be highly enhanced under various neuropathological conditions, causing increased oxidative stress and favoring abnormal metal-protein interactions. Intriguingly, despite the fact that most common NDs have a distinct etiological basis, they share striking similarities as they are all characterized by a documented brain metal impairment. This review will primarily focus on the alterations of metal homeostasis that are observed in normal aging and in Alzheimer's disease. We also present a brief survey on BMD in other NDs (Amyotrophic Lateral Sclerosis, Parkinson's, and Prion Protein disease) in order to highlight what represents the most reliable evidence supporting a crucial involvement of metals in neurodegeneration. The opportunities for metal-targeted pharmacological strategies in the major NDs are briefly outlined as well.

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Section: Zincmentioning

confidence: 97%

Metal Ion Physiopathology in Neurodegenerative Disorders

2009

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“…The difference in magnitude can be explained by methodological differences; the former measured chelatable levels, whereas the latter measured total tissue zinc isotope contents. Moreover, diet and drinking water in rodents have been shown to influence brain zinc levels (32,33), making whole brain tissue analysis of trace metals from rodents more prone to variability in comparison with cultured cells where known amounts of trace metals are found in media or buffers. Nevertheless, we clearly established that abnormal Zn 2ϩ metabolism is present in MLIV cells.…”

Section: Discussionmentioning

confidence: 99%

Zinc Dyshomeostasis Is Linked with the Loss of Mucolipidosis IV-associated TRPML1 Ion Channel

Eichelsdoerfer

Evans

Slaugenhaupt

et al. 2010

Journal of Biological Chemistry

102

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Chelatable zinc is important in brain function, and its homeostasis is maintained to prevent cytotoxic overload. However, certain pathologic events result in intracellular zinc accumulation in lysosomes and mitochondria. Abnormal lysosomes and mitochondria are common features of the human lysosomal storage disorder known as mucolipidosis IV (MLIV). MLIV is caused by the loss of TRPML1 ion channel function. MLIV cells develop large hyperacidic lysosomes, membranous vacuoles, mitochondrial fragmentation, and autophagic dysfunction. Here, we observed that RNA interference of mucolipin-1 gene (TRPML1) in HEK-293 cells mimics the MLIV cell phenotype consisting of large lysosomes and membranous vacuoles that accumulate chelatable zinc. To show that abnormal chelatable zinc levels are indeed correlated with MLIV pathology, we quantified its concentration in cultured MLIV patient fibroblast and control cells with a spectrofluorometer using N-(6-methoxy-8-quinolyl)-p-toluene sulfonamide fluorochrome. We found a significant increase of chelatable zinc levels in MLIV cells but not in control cells. Furthermore, we quantified various metal isotopes in whole brain tissue of TRPML1 ؊/؊ null mice and wild-type littermates using inductively coupled plasma mass spectrometry and observed that the zinc-66 isotope is markedly elevated in the brain of TRPML1 ؊/؊ mice when compared with controls. In conclusion, we show for the first time that the loss of TRPML1 function results in intracellular chelatable zinc dyshomeostasis. We propose that chelatable zinc accumulation in large lysosomes and membranous vacuoles may contribute to the pathogenesis of the disease and progressive cell degeneration in MLIV patients.Zinc (Zn 2ϩ ) is a redox-inert yet crucial trace element for virtually all organisms. Zn 2ϩ is second to iron in biological trace metal abundance and is known to play an important role in human brain function (1, 2). Some enzymes require Zn 2ϩ as co-factors, but many proteins use it for structural stability and thus are tightly bound (non-chelatable form) (3). A chelatable pool of Zn 2ϩ is present in cells, most notably in glutamatergic vesicles, and gets released at the neuronal synapse during normal and pathological states (4, 5). Because high levels of chelatable Zn 2ϩ or any trace metals produce cellular and mitochondrial toxicity (1, 6, 7), it is imperative that Zn 2ϩ homeostasis is actively maintained inside and outside of the cells. Certain pathological events such as epilepsy, cerebral stroke, and traumatic brain injury result in uncontrolled release and accumulation of chelatable Zn 2ϩ in neurons (1, 8) via voltage-gated or calcium-permeable ion channels (9). Furthermore, endosomes, autophagosomes, and lysosomes, which are critical organelles involved in the recycling and degradation of many proteins, are known compartments where chelatable Zn 2ϩ accumulates upon cellular perturbation (10 -12). Interestingly, chelatable Zn 2ϩ appears to mediate vacuolar formation in primary retinal cells exposed to ethambutol (an anti...

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“…Furthermore, dietary zinc deficiency exacerbated behavioral and histological pathology in an APP mutant mouse (Stoltenberg et al 2007), and zinc supplementation prevented AD pathology in the 3X-Tg mouse model (Corona et al 2010). However, another study found impaired memory performance in zinc supplemented APP mutant mice associated with decreased Ab deposition (Linkous et al 2009). …”

Section: Therapies Aimed At Modulating Zinc Availabilitymentioning

confidence: 99%

Zinc and the aging brain

Nuttall

Oteiza

2013

Genes Nutr

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Alterations in trace element homeostasis could be involved in the pathology of dementia, and in particular of Alzheimer's disease (AD). Zinc is a structural or functional component of many proteins, being involved in numerous and relevant physiological functions. Zinc homeostasis is affected in the elderly, and current evidence points to alterations in the cellular and systemic distribution of zinc in AD. Although the association of zinc and other metals with AD pathology remains unclear, therapeutic approaches designed to restore trace element homeostasis are being tested in clinical trials. Not only could zinc supplementation potentially benefit individuals with AD, but zinc supplementation also improves glycemic control in the elderly suffering from diabetes mellitus. However, the findings that select genetic polymorphisms may alter an individual's zinc intake requirements should be taken into consideration when planning zinc supplementation. This review will focus on current knowledge regarding pathological and protective mechanisms involving brain zinc in AD to highlight areas where future research may enable development of new and improved therapies.

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The Effects of Enhanced Zinc on Spatial Memory and Plaque Formation in Transgenic Mice

Cited by 54 publications

References 30 publications

Metal Ion Physiopathology in Neurodegenerative Disorders

Metal Ion Physiopathology in Neurodegenerative Disorders

Zinc Dyshomeostasis Is Linked with the Loss of Mucolipidosis IV-associated TRPML1 Ion Channel

Zinc and the aging brain

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