bims-metalz 2023-12-17 papers

Issue of 2023‒12‒17
three papers selected by
Mikaila Chetty, Goa University

Redox Biol. 2023 Dec 09. pii: S2213-2317(23)00391-9. [Epub ahead of print]69 102990

Lead aggravates Alzheimer's disease pathology via mitochondrial copper accumulation regulated by COX17.

Dingbang Huang, Lixuan Chen, Qiuyi Ji, Yang Xiang, Qin Zhou, Kaiju Chen, Xiaoshun Zhang, Fei Zou, Xingmei Zhang, Zaihua Zhao, Tao Wang, Gang Zheng, Xiaojing Meng.

Alzheimer's disease (AD) is a common neurodegenerative disease that is associated with multiple environmental risk factors, including heavy metals. Lead (Pb) is a heavy metal contaminant, which is closely related to the incidence of AD. However, the research on the role of microglia in Pb-induced AD-like pathology is limited. To determine the mechanism by which Pb exposure aggravates AD progression and the role of microglial activation, we exposed APP/PS1 mice and Aβ1-42-treated BV-2 cells to Pb. Our results suggested that chronic Pb exposure exacerbated learning and memory impairments in APP/PS1 mice. Pb exposure increased the activation of microglia in the hippocampus of APP/PS1 mice, which was associated with increased deposition of Aβ1-42, and induced hippocampal neuron damage. Pb exposure upregulated copper transporter 1 (CTR1) and downregulated copper P-type ATPase transporter (ATP7A) in the hippocampus of APP/PS1 mice and Aβ1-42-treated BV-2 cells. Moreover, Pb enhanced mitochondrial translocation of the mitochondrial copper transporter COX17, leading to an increase in mitochondrial copper concentration and mitochondrial damage. This could be reversed by copper-chelating agents or by inhibiting the mitochondrial translocation of COX17. The increased mitochondrial copper concentration caused by increased mitochondrial translocation of COX17 after Pb exposure may be related to the enhanced mitochondrial import pathway of AIF/CHCHD4. These results indicate that Pb induces the activation of microglia by increasing the concentration of copper in the mitochondria of microglia, and microglia release inflammatory factors to promote neuroinflammation, thus aggravating the pathology of AD. The present study provides new ideas for the prevention of Pb-induced AD.

Keywords: Alzheimer's disease; Microglia; Mitochondrial ROS; Mitochondrial copper; Pb

DOI: https://doi.org/10.1016/j.redox.2023.102990

Neurotoxicology. 2023 Dec 07. pii: S0161-813X(23)00152-3. [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.

Keywords: C. elegans; dopaminergic degeneration; microfluidics; quantitative image analysis; swimming-induced paralysis

DOI: https://doi.org/10.1016/j.neuro.2023.12.005

Epigenomics. 2023 Dec 13.

Gut microbiota defined epigenomes of Alzheimer's and Parkinson's diseases reveal novel targets for therapy.

Shabnam Nohesara, Hamid Mostafavi Abdolmaleky, Sam Thiagalingam, Jin-Rong Zhou.

The origins of Alzheimer's disease (AD) and Parkinson's disease (PD) involve genetic mutations, epigenetic changes, neurotoxin exposure and gut microbiota dysregulation. The gut microbiota's dynamic composition and its metabolites influence intestinal and blood-brain barrier integrity, contributing to AD and PD development. This review explores protein misfolding, aggregation and epigenetic links in AD and PD pathogenesis. It also highlights the role of a leaky gut and the microbiota-gut-brain axis in promoting these diseases through inflammation-induced epigenetic alterations. In addition, we investigate the potential of diet, probiotics and microbiota transplantation for preventing and treating AD and PD via epigenetic modifications, along with a discussion related to current challenges and future considerations. These approaches offer promise for translating research findings into practical clinical applications.

Keywords: Alzheimer's disease; Parkinson's diseases; epigenetic; leaky gut; microbiota; probiotics

DOI: https://doi.org/10.2217/epi-2023-0342