Transition metal abnormalities in progressive dementias

Akatsu, Hiroyasu; Hori, Akira; Yamamoto, Takayuki; Yoshida, Mari; Mimuro, Maya; Hashizume, Yoshio; Tooyama, Ikuo; Yezdimer, Eric M.

doi:10.1007/s10534-011-9504-8

Cited by 69 publications

(69 citation statements)

References 35 publications

(48 reference statements)

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“…This is in line with our previous observation that copper and zinc ions bind to the same site in the APP E2 domain (30). Physiological concentrations of free zinc ions generally exceed copper ion concentrations by magnitudes (42,43) due to the high number of copper chelation sites provided by proteins (44,45).…”

Section: Zinc Induces Oligomerization Of App Family Proteins In Cells-supporting

confidence: 92%

Novel Zinc-binding Site in the E2 Domain Regulates Amyloid Precursor-like Protein 1 (APLP1) Oligomerization

Mayer

Kaden

Schauenburg

et al. 2014

Journal of Biological Chemistry

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Background: Oligomeric complexes of APP, APLP1, and APLP2 contribute to synapse formation and structure. Results: Zinc binding to the E2 domain of APP and APLPs promotes their oligomerization in the cell, most notably with APLP1. Conclusion: Extracellular zinc is a regulator for structure and function of APP and APLPs. Significance: Novel insight into how APP and APLP function is regulated at the molecular level.

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Section: Zinc Induces Oligomerization Of App Family Proteins In Cells-supporting

confidence: 92%

Novel Zinc-binding Site in the E2 Domain Regulates Amyloid Precursor-like Protein 1 (APLP1) Oligomerization

Mayer

Kaden

Schauenburg

et al. 2014

Journal of Biological Chemistry

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“…[28][29][30][31][32][33] It is important to note though that these findings have not been universally consistent and may be influenced by methodological limitations and sample contamination. [34][35][36][37][38] Moreover, even if there is indeed higher levels of aluminum in the brains of AD sufferers, the temporal sequence and functional significance of such elevation remains unclear. For instance, it is entirely plausible that increased brain aluminum levels may reflect damage to the blood-brain barrier secondary to AD rather than being suggestive of any etiology.…”

Section: Discussionmentioning

confidence: 99%

Occupational Exposure to Aluminum and Alzheimer Disease

Virk

Eslick

2015

Journal of Occupational &Amp; Environmental Medicine

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Objective:We conducted a meta-analysis to systematically quantify the association between occupational exposure to aluminum and risk of Alzheimer disease (AD). Methods: Electronic database searches were conducted up to March 2015 for controlled studies. Study quality was assessed using the Newcastle-Ottawa Scale. Results: Three retrospective case-control studies, involving 1056 participants, met the criteria for inclusion. All studies used surrogate informants to ascertain exposure. Occupational aluminum exposure was not associated with AD (odds ratio, 1.00; 95% confidence interval, 0.59 to 1.68), even in sensitivity analysis excluding studies with low-quality assessment scores (odds ratio, 1.06; 95% confidence interval, 0.36 to 3.10). Conclusions:The findings of the present meta-analysis do not support a causative role of aluminum in the pathogenesis of AD. Nevertheless, in the absence of prospective studies with more precise ascertainment of exposure, a role for aluminum cannot be definitively excluded.A lzheimer disease (AD) accounts for 60% to 80% of dementia cases. 1 The worldwide prevalence of AD is projected to exceed 100 million by 2050, by which time 1 in 85 persons is expected to be living with this debilitating disease. 1 As current treatments for AD are unable to significantly modify disease progression, there has been growing interest in the identification of risk factors that may enable implementation of preventative strategies.Pathologically, AD is characterized by the aggregation of β-amyloid peptide in the form of neuritic plaques and the accumulation of hyperphosphorylated tau proteins as neurofibrillary tangles. 2 Nevertheless, a complete understanding of the mechanisms and factors underlying these changes remains elusive. Although AD is known to have a genetic component, epidemiological studies show more than two thirds of identical twins are discordant, indicating a significant etiological role for environmental factors. 3 Occupational exposures have garnered particular interest as the long prodromal phase of AD suggests the gradual effect or accumulation of a neurotoxin over many years. Previous meta-analyses have demonstrated an increased risk of AD with occupational exposure to low-frequency electromagnetic fields, 4 but no association with lead or industrial solvents. 5 Nevertheless, to date, the relationship between occupational exposure to aluminum and the risk of AD has not been systematically quantified.Aluminum is the most abundant metal in the Earth's crust, but the daily human intake in most countries is only in the order of a few milligrams. 6 Nevertheless, in individuals working in aluminumrelated industries, absorption from the nasal cavity may represent a significant additional source of aluminum exposure. 6 Olfactory neuron terminals within the nasal mucosa represents the only site where the central nervous system is directly exposed to the environment and inhalation of aluminum has been shown to markedly increase brain aluminum levels. 7 The present meta-analysis was thus con...

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“…However, AD is also associated with other metal imbalances such as major depression of copper levels and the issue of causality remains elusive (Akatsu et al, 2012;Exley et al, 2012).…”

Section: Inflammation Is Pronounced In the Aging Brain And This Is Fmentioning

confidence: 99%

Low levels of aluminum can lead to behavioral and morphological changes associated with Alzheimer's disease and age-related neurodegeneration

Bondy

2016

NeuroToxicology

201

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Transition metal abnormalities in progressive dementias

Cited by 69 publications

References 35 publications

Novel Zinc-binding Site in the E2 Domain Regulates Amyloid Precursor-like Protein 1 (APLP1) Oligomerization

Novel Zinc-binding Site in the E2 Domain Regulates Amyloid Precursor-like Protein 1 (APLP1) Oligomerization

Occupational Exposure to Aluminum and Alzheimer Disease

Low levels of aluminum can lead to behavioral and morphological changes associated with Alzheimer's disease and age-related neurodegeneration

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