bims-metalz 2023-09-10 papers

bims-metalz

Biomed News

on Metabolic causes of Alzheimer’s disease

Issue of 2023–09–10
six papers selected by
Mikaila Chetty, Goa University

[Relationships between microbiome and neurodegeneration].
Co-exposure to low-dose lead, cadmium, and mercury promotes memory deficits in rats: Insights from the dynamics of dendritic spine pruning in brain development.
Morphological hallmarks of dopaminergic neurodegeneration are associated with altered neuron function in Caenorhabditis elegans.
Gut Microbial Metabolome and Dysbiosis in Neurodegenerative Diseases: Psychobiotics and Fecal Microbiota Transplantation as a Therapeutic Approach-A Comprehensive Narrative Review.
Mitochondria in the Spotlight: C. elegans as a Model Organism to Evaluate Xenobiotic-Induced Dysfunction.
Selenium and zinc alleviate hepatotoxicity induced by heavy metal mixture (cadmium, mercury, lead and arsenic) via attenuation of inflammo-oxidant pathways.

Nervenarzt. 2023 Sep 06.

[Relationships between microbiome and neurodegeneration].

Corinna Bang, Sebastian Heinzel.

   BACKGROUND: Neurodegenerative diseases are often associated with changes in the (gut) microbiome.
OBJECTIVE: Based on studies in Parkinson's disease (PD) and Alzheimer's disease (AD), an overview of the current evidence of microbial changes and their possible role in the development of these diseases is given.
METHODS: Analysis, summary, and evaluation of the current literature on (gut) microbiome and neurodegeneration.
RESULTS: Numerous studies have shown dysbiotic changes in the gut microbiome of PD and AD patients compared to healthy individuals, some of which might occur even in the prodromal phase. Specifically, these patients show a reduction in bacteria involved in the synthesis of short-chain fatty acids. These microbial alterations have been associated with systemic inflammation and a compromised integrity of the intestinal barrier and blood-brain barrier. Bacterial molecules such as lipopolysaccharides may play an important role in these changes. Additionally, the bacterial protein curli, found on the surface of e.g., Escherichia coli, has been shown in vitro and in animal models to promote the misfolding of α-synuclein, thus suggesting a crucial pathomechanism. Moreover, certain oral bacteria appear to be more prevalent in AD patients and may contribute to the pathogenesis of AD.
CONCLUSION: Neurodegenerative diseases are associated with dysbiosis of the (gut) microbiome, which can have diverse systemic effects; however, it remains unclear whether this dysbiosis is a cause or a consequence of the diseases. Further investigation of this (prodromal) microbial imbalance could reveal new approaches for targeted therapeutic manipulation of the microbiome to modify and prevent these diseases.

Keywords:  Alzheimerʼs disease; Gut bacteria; Gut-brain axis; Parkinsonʼs disease; Therapeutic options

DOI:  https://doi.org/10.1007/s00115-023-01537-w
Ecotoxicol Environ Saf. 2023 Sep 01. pii: S0147-6513(23)00929-6. [Epub ahead of print]264 115425

Co-exposure to low-dose lead, cadmium, and mercury promotes memory deficits in rats: Insights from the dynamics of dendritic spine pruning in brain development.

Fankun Zhou, Lu Ouyang, Jie Xie, Sisi Liu, Qi Li, Shuo Yang, Jiajun Li, Rui Su, Shaoqi Rao, Lingyu Yan, Xin Wan, Hui Cheng, Peishan Liu, Lingling Li, Yanhui Zhu, Guihua Du, Chang Feng, Guangqin Fan.

  Lead (Pb), cadmium (Cd), and mercury (Hg) are environmentally toxic heavy metals that can be simultaneously detected at low levels in the blood of the general population. Although our previous studies have demonstrated neurodevelopmental toxicity upon co-exposure to these heavy metals at these low levels, the precise mechanisms remain largely unknown. Dendritic spines are the structural foundation of memory and undergo significant dynamic changes during development. This study focused on the dynamics of dendritic spines during brain development following Pb, Cd, and Hg co-exposure-induced memory impairment. First, the dynamic characteristics of dendritic spines in the prefrontal cortex were observed throughout the life cycle of normal rats. We observed that dendritic spines increased rapidly from birth to their peak value at weaning, followed by significant pruning and a decrease during adolescence. Dendritic spines tended to be stable until their loss in old age. Subsequently, a rat model of low-dose Pb, Cd, and Hg co-exposure from embryo to adolescence was established. The results showed that exposure to low doses of heavy metals equivalent to those detected in the blood of the general population impaired spatial memory and altered the dynamics of dendritic spine pruning from weaning to adolescence. Proteomic analysis of brain and blood samples suggested that differentially expressed proteins upon heavy metal exposure were enriched in dendritic spine-related cytoskeletal regulation and axon guidance signaling pathways and that cofilin was enriched in both of these pathways. Further experiments confirmed that heavy metal exposure altered actin cytoskeleton dynamics and disturbed the dendritic spine pruning-related LIM domain kinase 1-cofilin pathway in the rat prefrontal cortex. Our findings demonstrate that low-dose Pb, Cd, and Hg co-exposure may promote memory impairment by perturbing dendritic spine dynamics through dendritic spine pruning-related signaling pathways.

Keywords:  Dendritic spine dynamics; Heavy metal mixture; Human environmental exposure levels; Memory deficits

DOI:  https://doi.org/10.1016/j.ecoenv.2023.115425
bioRxiv. 2023 Aug 23. pii: 2023.08.22.554364. [Epub ahead of print]

Morphological hallmarks of dopaminergic neurodegeneration are associated with altered neuron function in Caenorhabditis elegans.

Andrew S Clark, Javier Huayta, Katherine S Morton, Joel N Meyer, Adriana San-Miguel.

Caenorhabditis elegans ( C. elegans ) is an excellent model system to study neurodegenerative diseases, such as Parkinson's disease, as it enables analysis of both neuron morphology and function in live animals. Multiple structural changes in neurons, such as cephalic dendrite morphological abnormalities, have been considered hallmarks of neurodegeneration in this model, but their relevance to changes in neuron function are not entirely clear. We sought to test whether hallmark morphological changes associated with chemically induced dopaminergic neuron degeneration, such as dendrite blebbing, breakage, and loss, are indicative of neuronal malfunction and result in changes in behavior. We adapted an established dopaminergic neuronal function assay by measuring paralysis in the presence of exogenous dopamine, which revealed clear differences between cat-2 dopamine deficient mutants, wildtype worms, and dat-1 dopamine abundant mutants. Next, we integrated an automated image processing algorithm and a microfluidic device to segregate worm populations by their cephalic dendrite morphologies. We show that nematodes with dopaminergic dendrite degeneration markers, such as blebbing or breakage, paralyze at higher rates in a dopamine solution, providing evidence that dopaminergic neurodegeneration morphologies are correlated with functional neuronal outputs.

DOI: https://doi.org/10.1101/2023.08.22.554364
Int J Mol Sci. 2023 Aug 27. pii: 13294. [Epub ahead of print]24(17):

Gut Microbial Metabolome and Dysbiosis in Neurodegenerative Diseases: Psychobiotics and Fecal Microbiota Transplantation as a Therapeutic Approach-A Comprehensive Narrative Review.

Sara Uceda, Víctor Echeverry-Alzate, Manuel Reiriz-Rojas, Esther Martínez-Miguel, Ana Pérez-Curiel, Silvia Gómez-Senent, Ana Isabel Beltrán-Velasco.

  The comprehensive narrative review conducted in this study delves into the mechanisms of communication and action at the molecular level in the human organism. The review addresses the complex mechanism involved in the microbiota-gut-brain axis as well as the implications of alterations in the microbial composition of patients with neurodegenerative diseases. The pathophysiology of neurodegenerative diseases with neuronal loss or death is analyzed, as well as the mechanisms of action of the main metabolites involved in the bidirectional communication through the microbiota-gut-brain axis. In addition, interventions targeting gut microbiota restructuring through fecal microbiota transplantation and the use of psychobiotics-pre- and pro-biotics-are evaluated as an opportunity to reduce the symptomatology associated with neurodegeneration in these pathologies. This review provides valuable information and facilitates a better understanding of the neurobiological mechanisms to be addressed in the treatment of neurodegenerative diseases.

Keywords:  dysbiosis; fecal microbiota transplantation; interventions; metabolites; microbiota; neurodegenerative diseases; prebiotics; probiotics; psychobiotics

DOI:  https://doi.org/10.3390/ijms241713294
Cells. 2023 Aug 22. pii: 2124. [Epub ahead of print]12(17):

Mitochondria in the Spotlight: C. elegans as a Model Organism to Evaluate Xenobiotic-Induced Dysfunction.

Airton C Martins, Miriam B Virgolini, Daiana Silva Ávila, Pablo Scharf, Jung Li, Alexey A Tinkov, Anatoly V Skalny, Aaron B Bowman, João B T Rocha, Michael Aschner.

  Mitochondria play a crucial role in cellular respiration, ATP production, and the regulation of various cellular processes. Mitochondrial dysfunctions have been directly linked to pathophysiological conditions, making them a significant target of interest in toxicological research. In recent years, there has been a growing need to understand the intricate effects of xenobiotics on human health, necessitating the use of effective scientific research tools. Caenorhabditis elegans (C. elegans), a nonpathogenic nematode, has emerged as a powerful tool for investigating toxic mechanisms and mitochondrial dysfunction. With remarkable genetic homology to mammals, C. elegans has been used in studies to elucidate the impact of contaminants and drugs on mitochondrial function. This review focuses on the effects of several toxic metals and metalloids, drugs of abuse and pesticides on mitochondria, highlighting the utility of C. elegans as a model organism to investigate mitochondrial dysfunction induced by xenobiotics. Mitochondrial structure, function, and dynamics are discussed, emphasizing their essential role in cellular viability and the regulation of processes such as autophagy, apoptosis, and calcium homeostasis. Additionally, specific toxins and toxicants, such as arsenic, cadmium, and manganese are examined in the context of their impact on mitochondrial function and the utility of C. elegans in elucidating the underlying mechanisms. Furthermore, we demonstrate the utilization of C. elegans as an experimental model providing a promising platform for investigating the intricate relationships between xenobiotics and mitochondrial dysfunction. This knowledge could contribute to the development of strategies to mitigate the adverse effects of contaminants and drugs of abuse, ultimately enhancing our understanding of these complex processes and promoting human health.

Keywords:  C. elegans; arsenic; cadmium; ethanol; manganese; mercury; mitochondria; pesticides

DOI:  https://doi.org/10.3390/cells12172124
Environ Toxicol. 2023 Sep 07.

Selenium and zinc alleviate hepatotoxicity induced by heavy metal mixture (cadmium, mercury, lead and arsenic) via attenuation of inflammo-oxidant pathways.

Harrison Ozoani, Anthonet N Ezejiofor, Kenneth O Okolo, Chinna N Orish, Ana Cirovic, Aleksandar Cirovic, Orish E Orisakwe.

  Heavy metals (HM) are believed to be injurious to humans. Man is exposed to them on daily basis unknowingly, with no acceptable protocol to manage its deleterious effects. These metals occur as mixture of chemicals with varying concentrations in our atmosphere. There are growing calls for the use of essential metals in mitigating the injurious effects induced by heavy metals exposure to man; therefore, the aim of this study was to evaluate the protective effects of essential metals (Zinc and Selenium) in a mixture of heavy metal toxicity. In this study, except for negative controls, all other groups were treated with lead (PbCl2 , 20 mg kg-1 ); cadmium (CdCl2 , 1.61 mg kg-1 ); mercury (HgCl2 , 0.40 mg kg-1 ), and arsenic (NaAsO3, 10 mg kg-1 ) that were formed in distilled water. Pb, Cd, As, and Hg were administered as mixtures to 35, 6 weeks old rats weighing between 80 to 100 g for 60 days. Group I served as normal control without treatment, group II positive control received HM mixture, while groups III to V received HMM with Zn, Se, and Zn + Se respectively. Animal and liver weights, HM accumulation in the liver, food intake (FI), water intake (WI), liver function test, malondialdehyde (MDA), and inflammatory/transcription factor/apoptosis markers were checked. Also, antioxidant enzymes, and histological studies were carried out. Metal mixture accumulated in the liver and caused toxicities which were ameliorated by Zn and Se administration. HM caused significant decrease in FI, WI and distorted the level of liver enzymes, lipid peroxidation, inflammatory markers, antioxidants and architecture of the liver. Co administration with Zn or Se or both reversed the distortions. This study lays credence to the evolving research on the public health implications of low dose metal mixtures and the possible ameliorative properties of Zn and Se.

Keywords:  arsenic; cadmium; hepatotoxicity; lead; selenium; zinc

DOI:  https://doi.org/10.1002/tox.23966