Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice

Lee, Joo‐Yong; Cole, Toby B.; Palmiter, Richard D.; Suh, Sang Won; Koh, Jae‐Young

doi:10.1073/pnas.092034699

Cited by 398 publications

(297 citation statements)

References 43 publications

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“…The question therefore arises as to whether elevated Zn levels contribute to lowering CNS A␤. However, studies in vitro and of synaptic zinc in vivo strongly indicate a pro-amyloidogenic effect of this abundant metal (13,15,53), excluding this possibility. How might elevated Cu modulate A␤ burden?…”

Section: Discussionmentioning

confidence: 98%

In vivo reduction of amyloid-β by a mutant copper transporter

Phinney

Drisaldi

Schmidt

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

204

153

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Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-␤ (A␤) peptide. To explore this relationship in vivo, toxic-milk (tx J ) mice with a mutant ATPase7b transporter favoring elevated Cu levels were analyzed in combination with the transgenic (Tg) CRND8 amyloid precursor protein mice exhibiting robust A␤ deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive tx J mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma A␤ levels. In addition, homozygosity for tx J increased survival of young TgCRND8 mice and lowered endogenous CNS A␤ at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the tx J mutation on CNS A␤ burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of A␤ peptide. A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by extracellular deposition of amyloid-␤ (A␤) as senile plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles (1). A␤ is generated by secretase-mediated endoproteolysis of the amyloid precursor protein (APP), and familial AD mutations skew APP processing to favor production of pro-amyloidogenic forms of the peptide or net A␤ production and thus drive disease pathogenesis. Although there is growing interest in defining pathogenic subvarieties of A␤ [e.g., secreted oligomeric assemblies such as A␤-derived diffusible ligands (2) and intracellular forms (3)], modulators of APP and A␤ biology in sporadic disease have remained more elusive. One area of particular interest concerns the role of transition metals.Cu and Zn ions are abundant in the normal brain (4-6), and direct measurements of metal levels have indicated altered homeostasis in AD (7-10). Interestingly, APP has a selective, high-affinity Cu-binding site in the extracellular (ecto-) domain that is capable of reducing Cu(II) to Cu(I) (11), and a recent structural analysis of this domain has revealed some similarity to previously identified Cu chaperone proteins (12). In addition to the ectodomain Cu-binding site of APP, A␤ peptide also contains binding sites for . A␤-metal interaction may drive both fibril formation and free radical production (13,(16)(17)(18), findings potentially relevant to AD pathogenesis in vivo, given that metal chelators can resolubilize A␤ aggregates from postmortem AD brain (19). On the other hand, studies of APP processing in cultured cells have revealed stimulation of the ␣-secretase pathway for APP processing by extracellular Cu ions (20). As this pathway cleaves the A␤ domain of APP into two fragments, it has a potential to be anti-amyloidogenic. Prompted by these divergent observations, we devised a genetic experiment to investigate how Cu might modulate A␤-dependent pathologies in vivo by using the transgenic (Tg) CRND8 line of TgAPP mice (21,22) in conjunction with a mutant allele of the CuATPase7b c...

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Section: Discussionmentioning

confidence: 98%

In vivo reduction of amyloid-β by a mutant copper transporter

Phinney

Drisaldi

Schmidt

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

204

153

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“…ZnT3 traffics zinc into synaptic vesicles and zinc is released into the synapse upon exocytosis. APP transgenic mice crossed with mice lacking ZnT3 were shown to have reduced plaque burden compared with single transgenic mice [84], which demonstrates the contribution of endogenous zinc to amyloid burden in AD. Zinc "trapping" in amyloid plaque is also likely to be deleterious to synaptic function as loss of synaptic zinc in ZnT3 KO mice causes impaired cognition, recapitulating AD [85].…”

Section: Zincmentioning

confidence: 90%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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“…(3) Zinc stimulates kinases and inhibits protein phosphatases leading to phosphorylation of Tau which promotes the aggregation of Tau in neurofibrillary tangles (NFT) and contributes to a positive feedback loop that further increases postsynaptic calcium influx through NMDARs resulting in neuronal cell death synaptic activity in the APP/PS1 mouse model and direct application of soluble Ab dimers to CA1 neurons increases synaptic activity in wild type mice measured in vivo by calcium imaging (Busche et al 2012). Deficiency of the zinc transporter ZnT3 or the brain specific zinc binding protein metallothionein (MT)3 can prevent deposition of Ab in Swedish mutant APP mice (Lee et al 2002;Manso et al 2012), and senile plaques form preferentially in zinc enriched cortical layers of APP/PS1 mice (Stoltenberg et al 2007). These findings provide further evidence that zinc released from synaptic vesicles could contribute to AD pathology.…”

Section: Risk Of Zinc Deficiency In the Elderlymentioning

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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Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice

Cited by 398 publications

References 43 publications

In vivo reduction of amyloid-β by a mutant copper transporter

In vivo reduction of amyloid-β by a mutant copper transporter

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Zinc and the aging brain

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