bims-metalz 2023-10-29 papers

bims-metalz

Biomed News

on Metabolic causes of Alzheimer’s disease

Issue of 2023–10–29
nine papers selected by
Mikaila Chetty, Goa University

Elegant Nematodes Improve Our Understanding of Human Neuronal Diseases, the Role of Pollutants and Strategies of Resilience.
Gut microbiota-derived short chain fatty acids act as mediators of the gut-brain axis targeting age-related neurodegenerative disorders: a narrative review.
Effects of Redox Homeostasis and Mitochondrial Damage on Alzheimer's Disease.
Cytochrome P450 and Epoxide Hydrolase Metabolites in Aβ and tau-induced Neurodegeneration: Insights from Caenorhabditis elegans.
Towards generalization for Caenorhabditis elegans detection.
Reactive oxygen species drive foraging decisions in Caenorhabditis elegans.
Effect of altered production and storage of dopamine on development and behavior in C. elegans.
Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend C. elegans Life- and Healthspan.
Physiological Effects of Oxidative Stress Caused by Saxitoxin in the Nematode Caenorhabditis elegans.

Environ Sci Technol. 2023 Oct 24.

Elegant Nematodes Improve Our Understanding of Human Neuronal Diseases, the Role of Pollutants and Strategies of Resilience.

Anna von Mikecz.

  The prevalence of neurodegenerative disorders such as Alzheimer's and Parkinson's disease are rising globally. The role of environmental pollution in neurodegeneration is largely unknown. Thus, this perspective advocates exposome research in C. elegans models of human diseases. The models express amyloid proteins such as Aβ, recapitulate the degeneration of specifically vulnerable neurons and allow for correlated neurobehavioral phenotyping throughout the entire life span of the nematode. Neurobehavioral traits like locomotion gaits, rigidity, or cognitive decline are quantifiable and carefully mimic key aspects of the human diseases. Underlying molecular pathways of neurodegeneration are elucidated in pollutant-exposed C. elegans Alzheimer's or Parkinson's models by transcriptomics (RNA-seq), mass spectrometry-based proteomics and omics addressing other biochemical traits. Validation of the identified disease pathways can be achieved by genome-wide association studies in matching human cohorts. A consistent One Health approach includes isolation of nematodes from contaminated sites and their comparative investigation by imaging, neurobehavioral profiling and single worm proteomics. C. elegans models of neurodegenerative diseases are likewise well-suited for high throughput methods that provide a promising strategy to identify resilience pathways of neurosafety and keep up with the number of pollutants, nonchemical exposome factors, and their interactions.

Keywords:  Caenorhabditis elegans; aging; air pollution; climate change; nanoparticles; neurodegeneration; neuropeptides; neurotoxicity

DOI:  https://doi.org/10.1021/acs.est.3c04580
Crit Rev Food Sci Nutr. 2023 Oct 27. 1-22

Gut microbiota-derived short chain fatty acids act as mediators of the gut-brain axis targeting age-related neurodegenerative disorders: a narrative review.

Bingbing Guo, Jingyi Zhang, Weihao Zhang, Feng Chen, Bin Liu.

  Neurodegenerative diseases associated with aging are often accompanied by cognitive decline and gut microbiota disorder. But the impact of gut microbiota on these cognitive disturbances remains incompletely understood. Short chain fatty acids (SCFAs) are major metabolites produced by gut microbiota during the digestion of dietary fiber, serving as an energy source for gut epithelial cells and/or circulating to other organs, such as the liver and brain, through the bloodstream. SCFAs have been shown to cross the blood-brain barrier and played crucial roles in brain metabolism, with potential implications in mediating Alzheimer's disease (AD) and Parkinson's disease (PD). However, the underlying mechanisms that SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, the dietary sources which determine these SCFAs production was not thoroughly evaluated yet. This comprehensive review explores the production of SCFAs by gut microbiota, their transportation through the gut-brain axis, and the potential mechanisms by which they influence age-related neurodegenerative disorders. Also, the review discusses the importance of dietary fiber sources and the challenges associated with harnessing dietary-derived SCFAs as promoters of neurological health in elderly individuals. Overall, this study suggests that gut microbiota-derived SCFAs and/or dietary fibers hold promise as potential targets and strategies for addressing age-related neurodegenerative disorders.

Keywords:  Dietary fiber; gut microbiota; gut–brain-axis; short chain fatty acids

DOI:  https://doi.org/10.1080/10408398.2023.2272769
Antioxidants (Basel). 2023 Sep 30. pii: 1816. [Epub ahead of print]12(10):

Effects of Redox Homeostasis and Mitochondrial Damage on Alzheimer's Disease.

Yi-Hsuan Wu, Hsi-Lung Hsieh.

  Bioenergetic mitochondrial dysfunction is a common feature of several diseases, including Alzheimer's disease (AD), where redox imbalance also plays an important role in terms of disease development. AD is an age-related disease and begins many years before the appearance of neurodegenerative symptoms. Intracellular tau aggregation, extracellular β-amyloid (Aβ) deposition in the brain, and even the APOE4 genotype contribute to the process of AD by impairing redox homeostasis and mitochondrial dysfunction. This review summarizes the evidence for the redox imbalance and mitochondrial dysfunction in AD and demonstrates the current therapeutic strategies related to mitochondrial maintenance.

Keywords:  APOE4; Alzheimer’s disease; mitochondrial dysfunctions; redox homeostasis; tau; β-amyloid

DOI:  https://doi.org/10.3390/antiox12101816
bioRxiv. 2023 Oct 02. pii: 2023.10.02.560527. [Epub ahead of print]

Cytochrome P450 and Epoxide Hydrolase Metabolites in Aβ and tau-induced Neurodegeneration: Insights from Caenorhabditis elegans.

Morteza Sarparast, Jennifer Hinman, Elham Pourmand, Derek Vonarx, Leslie Ramirez, Wenjuan Ma, Nicole F Liachko, Jamie K Alan, Kin Sing Stephen Lee.

This study aims to uncover potent cytochrome P450 (CYP) and epoxide hydrolase (EH) metabolites implicated in Aβ and/or tau-induced neurodegeneration, independent of neuroinflammation, by utilizing Caenorhabditis elegans ( C. elegans ) as a model organism. Our research reveals that Aβ and/or tau expression in C. elegans disrupts the oxylipin profile, and epoxide hydrolase inhibition alleviates the ensuing neurodegeneration, likely through elevating the epoxy-to-hydroxy ratio of various CYP-EH metabolites. In addition, our results indicated that the Aβ and tau likely affect the CYP-EH metabolism of PUFA through different mechanism. These findings emphasize the intriguing relationship between lipid metabolites and neurodegenerations, in particular, those linked to Aβ and/or tau aggregation. Furthermore, our investigation sheds light on the crucial and captivating role of CYP PUFA metabolites in C. elegans physiology, opening up possibilities for broader implications in mammalian and human contexts.
Abstract Figure:

DOI: https://doi.org/10.1101/2023.10.02.560527
Comput Struct Biotechnol J. 2023 ;21 4914-4922

Towards generalization for Caenorhabditis elegans detection.

Santiago Escobar-Benavides, Antonio García-Garví, Pablo E Layana-Castro, Antonio-José Sánchez-Salmerón.

  The nematode Caenorhabditis elegans (C. elegans) is of significant interest for research into neurodegenerative diseases, aging, and drug screening. However, conducting these assays manually is a tedious and time-consuming process. This paper proposes a methodology to achieve a generalist C. elegans detection algorithm, as previous work only focused on dataset-specific detection, tailored exclusively to the characteristics and appearance of the images in a given dataset. The main aim of our study is to achieve a solution that allows for robust detection, regardless of the image-capture system used, with the potential to serve as a basis for the automation of numerous assays. These potential applications include worm counting, worm tracking, motion detection and motion characterization. To train this model, a dataset consisting of a wide variety of appearances adopted by C. elegans has been curated and dataset augmentation methods have been proposed and evaluated, including synthetic image generation. The results show that the model achieves an average precision of 89.5% for a wide variety of C. elegans appearances that were not used during training, thereby validating its generalization capabilities.

Keywords:  C. elegans; Detection network; YOLO

DOI:  https://doi.org/10.1016/j.csbj.2023.09.039
Redox Biol. 2023 Oct 13. pii: S2213-2317(23)00335-X. [Epub ahead of print]67 102934

Reactive oxygen species drive foraging decisions in Caenorhabditis elegans.

Andrew P Bischer, Timothy M Baran, Andrew P Wojtovich.

  Environmental surveillance-mediated behavior integrates multiple cues through complex signaling mechanisms. In Caenorhabditis elegans, neurons coordinate perception and response through evolutionarily conserved molecular signaling cascades to mediate attraction and avoidance behaviors. However, despite lacking eyes, C. elegans was recently reported to perceive and react to the color blue. Here, we provide an explanation for this apparent color perception. We show that internally-generated reactive oxygen species (ROS) occurring in response to light are additive to exogenous sources of ROS, such as bacterial toxins or photosensitizers. Multiple sub-threshold sources of ROS are integrated to coordinate behavioral responses to the environment with internal physiologic cues, independent of color. We further demonstrate that avoidance behavior can be blocked by antioxidants, while ROS is both sufficient and scalable to phenocopy the avoidance response. Moreover, avoidance behavior in response to ROS is plastic and reversible, suggesting it may occur through a post-translation redox modification. Blue light affects C. elegans behavior through ROS generation by endogenous flavins in a process requiring the neuronal gustatory photoreceptor like protein, LITE-1. Our results demonstrate that LITE-1 is also required for ROS-mediated avoidance of pyocyanin and light-activated photosensitizers and this role is mediated through the modification of Cys44. Overall, these findings demonstrate that ROS and LITE-1 are central mediators of C. elegans foraging behavior through integration of multiple inputs, including light.

Keywords:  Antioxidant; Caenorhabditis elegans; Mitochondria; Photosensitizer; Pyocyanin; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.redox.2023.102934
bioRxiv. 2023 Oct 10. pii: 2023.10.07.561350. [Epub ahead of print]

Effect of altered production and storage of dopamine on development and behavior in C. elegans.

Irene Lee, Ava C Knickerbocker, Charlotte Rose Depew, Elizabeth Martin, Jocelyn Dicent, Gary W Miller, Meghan L Bucher.

The nematode, Caenorhabditis elegans , is an advantageous model for studying developmental toxicology due to its homology to humans and well-defined developmental stages. Similarly to humans, C. elegans utilize dopamine as a neurotransmitter to regulate motor behavior. We have previously reported behavioral deficits in a genetic model of C. elegans (OK411) that lack the neurotransmitter transporter necessary for packaging dopamine into synaptic vesicles. Anecdotally, we observed these C. elegans appeared to have a smaller body size, which is supported by prior studies that observed a larger body size in C. elegans that lack the enzyme that catalyzes dopamine synthesis, suggesting a complex regulatory system in which dopamine mediates body size in C. elegans . However, the question of whether body size abnormalities apparent in C. elegans with disruptions to their dopamine system are developmental or purely based on body size remains unanswered. Here, we present data characterizing the effect of gene mutations in dopamine-related proteins on body size, development, and behavior. We analyzed C. elegans that lack the ability to sequester dopamine (OK411), that overproduce dopamine (UA57), and a novel strain (MBIA) generated through crossing OK411 and UA57, which lacks the ability to sequester dopamine into vesicles and additionally endogenously overproduces dopamine. This novel strain was generated to address the hypothesis that an endogenous increase in production of dopamine can rescue deficits caused by a lack of vesicular dopamine sequestration. Compared to wild type, OK411 have shorter body lengths and behavioral deficits in early life stages. In contrast, the MBIA strain have similar body lengths to wild-type by early adulthood and display similar behavior to wild-type by early adulthood. Our data suggests that endogenously increasing the production of dopamine is able to mitigate deficits in C. elegans lacking the ability to package dopamine into synaptic vesicles. These results provide evidence that the dopamine system impacts development, growth, and reproduction in C. elegans .

DOI: https://doi.org/10.1101/2023.10.07.561350
Pharmaceuticals (Basel). 2023 Oct 20. pii: 1498. [Epub ahead of print]16(10):

Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend C. elegans Life- and Healthspan.

Samuel Kakraba, Srinivas Ayyadevara, Nirjal Mainali, Meenakshisundaram Balasubramaniam, Suresh Bowroju, Narsimha Reddy Penthala, Ramani Atluri, Steven W Barger, Sue T Griffin, Peter A Crooks, Robert J Shmookler Reis.

  Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer's disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases. We screened a panel of bioactive thiadiazolidinones (TDZDs) from our in-house library for rescue of protein aggregation in human-cell and C. elegans models of neurodegeneration. Among the tested TDZD analogs, PNR886 and PNR962 were most effective, significantly reducing both the number and intensity of Alzheimer-like tau and amyloid aggregates in human cell-culture models of pathogenic aggregation. A C. elegans strain expressing human Aβ1-42 in muscle, leading to AD-like amyloidopathy, developed fewer and smaller aggregates after PNR886 or PNR962 treatment. Moreover, age-progressive paralysis was reduced 90% by PNR886 and 75% by PNR962, and "healthspan" (the median duration of spontaneous motility) was extended 29% and 62%, respectively. These TDZD analogs also extended wild-type C. elegans lifespan by 15-30% (p < 0.001), placing them among the most effective life-extension drugs. Because the lead drug in this family, TDZD-8, inhibits GSK3β, we used molecular-dynamic tools to assess whether these analogs may also target GSK3β. In silico modeling predicted that PNR886 or PNR962 would bind to the same allosteric pocket of inactive GSK3β as TDZD-8, employing the same pharmacophore but attaching with greater avidity. PNR886 and PNR962 are thus compelling candidate drugs for treatment of tau- and amyloid-associated neurodegenerative diseases such as AD, potentially also reducing all-cause mortality.

Keywords:  Alzheimer’s disease; aggregation; glycogen synthase kinase 3β (GSK3β); molecular modeling; neurodegeneration; neurodegenerative disease; protein aggregation; proteostasis; thiadiazolidinones (TDZDs)

DOI:  https://doi.org/10.3390/ph16101498
Mar Drugs. 2023 Oct 19. pii: 544. [Epub ahead of print]21(10):

Physiological Effects of Oxidative Stress Caused by Saxitoxin in the Nematode Caenorhabditis elegans.

Haiyan Wu, Balakrishnan Prithiviraj, Zhijun Tan.

  Saxitoxin (STX) causes high toxicity by blocking voltage-gated sodium channels, and it poses a major threat to marine ecosystems and human health worldwide. Our work evaluated the neurotoxicity and chronic toxicology of STX to Caenorhabditis elegans by an analysis of lifespan, brood size, growth ability, reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels, and the overexpression of green fluorescent protein (GFP). After exposure to a series of concentrations of STX for 24 h, worms showed paralysis symptoms and fully recovered within 6 h; less than 5% of worms died at the highest concentration of 1000 ng/mL for first larval stage (L1) worms and 10,000 ng/mL for fourth larval stage (L4) worms. Declines in lifespan, productivity, and body size of C. elegans were observed under the stress of 1, 10, and 100 ng/mL STX, and the lifespan was shorter than that in controls. With STX exposure, the productivity declined by 32-49%; the body size, including body length and body area, declined by 13-18% and 25-27%, respectively. The levels of ROS exhibited a gradual increase over time, accompanied by a positive concentration effect of STX resulting in 1.14-1.86 times higher levels compared to the control group in L4 worms. Conversely, no statistically significant differences were observed between L1 worms. Finally, after exposure to STX for 48 h, ATP levels and GFP expression in C. elegans showed a significant dose-dependent increase. Our study reports the first evidence that STX is not lethal but imposes substantial oxidative stress on C. elegans, with a dose-responsive relationship. Our results indicated that C. elegans is an ideal model to further study the mechanisms underlying the fitness of organisms under the stress caused by paralytic shellfish toxins including STX.

Keywords:  ATP; Caenorhabditis elegans; oxidative stress; reproductivity; saxitoxin

DOI:  https://doi.org/10.3390/md21100544