Circulatory Levels of Toxic Metals (Aluminum, Cadmium, Mercury, Lead) in Patients with Alzheimer’s Disease: A Quantitative Meta-Analysis and Systematic Review

Xu, Lin; Zhang, Wenchao; Liu, Xianchen; Zhang, Cuili; Wang, Pin; Zhao, Xianxian

doi:10.3233/jad-170811

Cited by 74 publications

(44 citation statements)

References 62 publications

(66 reference statements)

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“…Alzheimer's disease (AD) is the leading cause of dementia worldwide, and AD patients and their families urgently require novel therapeutics to prevent and slow the progression of this devastating disorder. Hallmarks of AD include amyloid-␤ (A␤) peptide secretion and deposition into neuritic plaques, tau protein hyperphosphorylation and neurofibrillary tangle formation, metal ion dyshomeostasis [1][2][3][4][5][6][7][8][9], oxidative stress and lipid, nucleic acid, and protein damage [10][11][12][13], abortive cell cycle reentry [14][15][16][17][18][19][20][21][22][23][24][25][26], neuroinflammation and microbial dysbiosis [27][28][29][30][31][32][33], insulin resistance [34,35], cerebrovascular dysfunction [36][37][38], synaptic dysfunction [39,40], neuronal loss, endoplasmic reticulum stress [41][42][43][44], and mitochondrial dysfunction [...…”

Section: Introductionmentioning

confidence: 99%

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Sanders

2020

ADR

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Nitric oxide/cyclic guanosine monophosphate (cGMP) signaling is compromised in Alzheimer's disease (AD), and phosphodiesterase 5 (PDE5), which degrades cGMP, is upregulated. Sildenafil inhibits PDE5 and increases cGMP levels. Integrating previous findings, we determine that most doses of sildenafil (especially low doses) likely activate peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC1␣) via protein kinase G-mediated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) phosphorylation and/or Sirtuin-1 activation and PGC1␣ deacetylation. Via PGC1␣ signaling, low-dose sildenafil likely suppresses ␤-secretase 1 expression and amyloid-␤ (A␤) generation, upregulates antioxidant enzymes, and induces mitochondrial biogenesis. Plus, sildenafil should increase brain perfusion, insulin sensitivity, long-term potentiation, and neurogenesis while suppressing neural apoptosis and inflammation. A systematic review of sildenafil in AD was undertaken. In vitro, sildenafil protected neural mitochondria from A␤ and advanced glycation end products. In transgenic AD mice, sildenafil was found to rescue deficits in CREB phosphorylation and memory, upregulate brain-derived neurotrophic factor, reduce reactive astrocytes and microglia, decrease interleukin-1␤, interleukin-6, and tumor necrosis factor-␣, decrease neural apoptosis, increase neurogenesis, and reduce tau hyperphosphorylation. All studies that tested A␤ levels reported significant improvements except the two that used the highest dosage, consistent with the doselimiting effect of cGMP-induced phosphodiesterase 2 (PDE2) activation and cAMP depletion on PGC1␣ signaling. In AD patients, a single dose of sildenafil decreased spontaneous neural activity, increased cerebral blood flow, and increased the cerebral metabolic rate of oxygen. A randomized control trial of sildenafil (ideally with a PDE2 inhibitor) in AD patients is warranted.

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Section: Introductionmentioning

confidence: 99%

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Sanders

2020

ADR

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“…Human epidemiological studies have showed that circulating levels of certain heavy metals are higher in patients with Alzheimer's disease than in control patients (Fathabadi et al 2018;Xu et al 2018). This suggests a potential role of heavy metals in Alzheimer's disease, but it is not yet clear whether they interfere in the development or the progression of the disease.…”

Section: Introductionmentioning

confidence: 99%

Fungicide Residues Exposure and β-amyloid Aggregation in a Mouse Model of Alzheimer’s Disease

Lafon

Wang

Arango-Lievano

et al. 2020

Environ Health Perspect

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BACKGROUND: Pesticide residues have contaminated our environment and nutrition over the last century. Although these compounds are present at very low concentrations, their long-term effects on human health is of concern. The link between pesticide residues and Alzheimer's disease is not clear and difficult to establish. To date, no in vivo experiments have yet modeled the impact of this chronic contamination on neurodegenerative disorders. OBJECTIVES: We investigated the impact of fungicide residues on the pathological markers of Alzheimer's disease in a transgenic mouse model. METHODS: Transgenic (J20, hAPP Sw=Ind) mice were chronically exposed to a cocktail of residues of cyprodinil, mepanipyrim, and pyrimethanil at 0:1 lg=L in their drinking water for 9 months. We assessed the effects of fungicide residues on the pathological markers of the disease including Ab aggregates, neuroinflammation, and neuronal loss. Then, we studied the dynamics of Ab aggregation in vivo via a longitudinal study using twophoton microscopy. Finally, we investigated the molecular mechanisms involved in the production and clearance of Ab peptides. RESULTS: We found that a chronic exposure to three fungicide residues exacerbated aggregation, microgliosis, and neuronal loss. These fungicides also increased vascular amyloid aggregates reminiscent of cerebral amyloid angiopathy between 6 and 9 months of treatment. The mechanism of action revealed that fungicides promoted Ab peptide fibril formation in vitro and involved an in vivo overexpression of the levels of the b-secretasecleaving enzyme (BACE1) combined with impairment of Ab clearance through neprylisin (NEP). CONCLUSIONS: Chronic exposure of the J20 mouse model of Alzheimer's disease to a cocktail of fungicides, at the regulatory concentration allowed in tap water (0:1 lg=L), strengthened the preexisting pathological markers: neuroinflammation, Ab aggregation, and APP b-processing. We hypothesize prevention strategies toward pesticide long-term exposure may be an alternative to counterbalance the lack of treatment and to slow down the worldwide Alzheimer's epidemic.

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“…Five fountains have high levels of Al that exceed the maximum allowable limits (200 µg/L) in the international standards for drinking water quality. There are studies reporting the neurotoxic effect of aluminium production, including high Al levels in the pathophysiology of Alzheimer's disease and it is defined as Group‐I carcinogenic by the IARC (; Marques et al ., ; Xu et al ., ).…”

Section: Resultsmentioning

confidence: 99%

A quality assessment of public water fountains and relation to human health: a case study from Yozgat, Turkey

İritaş

Türksoy

Deniz

et al. 2018

Water & Environment J

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Public fountains are very common and everyday people appreciate the benefits a water fountain can bring. However, consumption of public fountain water in some country has decreased because of growing concerns that constituents in fountain water may have adverse effects on health. A few studies have examined the safety of public fountains, proposing only limited evidence of fountain-related health issues in Turkey. Most of these public fountains are sourced from natural springs in Turkey. In this study, a 177 fountain water and 32 rock samples were analysed for source and quality of water. The geology of the region has the direct impact on the quality of the public fountain water. The results indicate that the level of some elements exceeded the limit values determined by WHO and US.EPA. The most striking high values were observed for iron (Fe), nickel (Ni), aluminum (Al), arsenic (As) and bromine (Br) concentrations.

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Circulatory Levels of Toxic Metals (Aluminum, Cadmium, Mercury, Lead) in Patients with Alzheimer’s Disease: A Quantitative Meta-Analysis and Systematic Review

Cited by 74 publications

References 62 publications

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Fungicide Residues Exposure and β-amyloid Aggregation in a Mouse Model of Alzheimer’s Disease

A quality assessment of public water fountains and relation to human health: a case study from Yozgat, Turkey

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