bims-metalz 2023-10-08 papers

bims-metalz

Biomed News

on Metabolic causes of Alzheimer’s disease

Issue of 2023–10–08
nine papers selected by
Mikaila Chetty, Goa University

Sink or swim: Does a worm paralysis phenotype hold clues to neurodegenerative disease?
The gut microbiome: an important role in neurodegenerative diseases and their therapeutic advances.
Advances in the study of the relationship between Alzheimer's disease and the gastrointestinal microbiome.
Regulation of defective mitochondrial DNA accumulation and transmission in C. elegans by the programmed cell death and aging pathways.
Caenorhabditis elegans as an in vivo model for the identification of natural antioxidants with anti-aging actions.
Prevention of Alzheimer's disease through diet: An exploratory review.
The Gut-brain Connection and Episodic Migraine: an Update.
Proteostasis is differentially modulated by inhibition of translation initiation or elongation.
RNA-Binding Proteins: A Role in Neurotoxicity?

J Cell Physiol. 2023 Oct 05.

Sink or swim: Does a worm paralysis phenotype hold clues to neurodegenerative disease?

Peter Rodriguez, Randy D Blakely.

  Receiving a neurodegenerative disease (NDD) diagnosis, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis, is devastating, particularly given the limited options for treatment. Advances in genetic technologies have allowed for efficient modeling of NDDs in animals and brought hope for new disease-modifying medications. The complexity of the mammalian brain and the costs and time needed to identify and develop therapeutic leads limits progress. Modeling NDDs in invertebrates, such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, offers orders of magnitude increases in speed of genetic analysis and manipulation, and can be pursued at substantially reduced cost, providing an important, platform complement and inform research with mammalian NDD models. In this review, we describe how our efforts to exploit C. elegans for the study of neural signaling and health led to the discovery of a paralytic phenotype (swimming-induced paralysis) associated with altered dopamine signaling and, surprisingly, to the discovery of a novel gene and pathway whose dysfunction in glial cells triggers neurodegeneration. Research to date on swip-10 and its putative mammalian ortholog MBLAC1, suggests that a tandem analysis will offer insights into NDD mechanisms and insights into novel, disease-modifying therapeutics.

Keywords:  Alzheimer's disease; C. elegans; MBLAC1; Parkinson's disease; glia; swip-10

DOI:  https://doi.org/10.1002/jcp.31125
Mol Cell Biochem. 2023 Oct 03.

The gut microbiome: an important role in neurodegenerative diseases and their therapeutic advances.

Songlin Li, Linna Zhao, Jie Xiao, Yuying Guo, Rong Fu, Yunsha Zhang, Shixin Xu.

  There are complex interactions between the gut and the brain. With increasing research on the relationship between gut microbiota and brain function, accumulated clinical and preclinical evidence suggests that gut microbiota is intimately involved in the pathogenesis of neurodegenerative diseases (NDs). Increasingly studies are beginning to focus on the association between gut microbiota and central nervous system (CNS) degenerative pathologies to find potential therapies for these refractory diseases. In this review, we summarize the changes in the gut microbiota in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis and contribute to our understanding of the function of the gut microbiota in NDs and its possible involvement in the pathogenesis. We subsequently discuss therapeutic approaches targeting gut microbial abnormalities in these diseases, including antibiotics, diet, probiotics, and fecal microbiota transplantation (FMT). Furthermore, we summarize some completed and ongoing clinical trials of interventions with gut microbes for NDs, which may provide new ideas for studying NDs.

Keywords:  Central neuroinflammation; Gut microbiota; Microbiota-gut-brain axis; Neurodegenerative diseases; Treatment

DOI:  https://doi.org/10.1007/s11010-023-04853-6
Ibrain. 2022 ;8(4): 465-475

Advances in the study of the relationship between Alzheimer's disease and the gastrointestinal microbiome.

Xin-Yan Li, Hao-Yue Qin, Ting-Ting Li.

  There are many trillions of bacteria in the gastrointestinal microbiome (GM). Their ecological dysregulation can contribute to the development of certain neurodegenerative diseases, including Alzheimer's disease (AD). AD is common dementia and its incidence is increasing year by year. However, the relationship between GM and AD is unclear. Therefore, this review discusses the relationship between GM and AD, elaborates on the possible factors that can affect this relationship through the inflammation of the brain induced by blood-brain damage and accumulation of amyloid deposit, and proposes feasible ways to treat AD through GM-related substances, such as probiotics, Mega-3, and gut hormones, including their shortcomings as well.

Keywords:  Alzheimer's disease; gastrointestinal microbiome; gut hormones; probiotics; short‐chain fatty acids

DOI:  https://doi.org/10.1002/ibra.12065
Elife. 2023 10 02. pii: e79725. [Epub ahead of print]12

Regulation of defective mitochondrial DNA accumulation and transmission in C. elegans by the programmed cell death and aging pathways.

Sagen Flowers, Rushali Kothari, Yamila N Torres Cleuren, Melissa R Alcorn, Chee Kiang Ewe, Geneva Alok, Samantha L Fiallo, Pradeep M Joshi, Joel H Rothman.

  The heteroplasmic state of eukaryotic cells allows for cryptic accumulation of defective mitochondrial genomes (mtDNA). 'Purifying selection' mechanisms operate to remove such dysfunctional mtDNAs. We found that activators of programmed cell death (PCD), including the CED-3 and CSP-1 caspases, the BH3-only protein CED-13, and PCD corpse engulfment factors, are required in C. elegans to attenuate germline abundance of a 3.1-kb mtDNA deletion mutation, uaDf5, which is normally stably maintained in heteroplasmy with wildtype mtDNA. In contrast, removal of CED-4/Apaf1 or a mutation in the CED-4-interacting prodomain of CED-3, do not increase accumulation of the defective mtDNA, suggesting induction of a non-canonical germline PCD mechanism or non-apoptotic action of the CED-13/caspase axis. We also found that the abundance of germline mtDNAuaDf5 reproducibly increases with age of the mothers. This effect is transmitted to the offspring of mothers, with only partial intergenerational removal of the defective mtDNA. In mutants with elevated mtDNAuaDf5 levels, this removal is enhanced in older mothers, suggesting an age-dependent mechanism of mtDNA quality control. Indeed, we found that both steady-state and age-dependent accumulation rates of uaDf5 are markedly decreased in long-lived, and increased in short-lived, mutants. These findings reveal that regulators of both PCD and the aging program are required for germline mtDNA quality control and its intergenerational transmission.

Keywords:  C. elegans; aging; cell biology; genetics; genomics; heteroplasmy; insulin signaling; programmed cell death; purifying selection; uaDf5

DOI:  https://doi.org/10.7554/eLife.79725
Biomed Pharmacother. 2023 Sep 28. pii: S0753-3322(23)01392-6. [Epub ahead of print]167 115594

Caenorhabditis elegans as an in vivo model for the identification of natural antioxidants with anti-aging actions.

Yugui Lin, Chunxiu Lin, Yong Cao, Yunjiao Chen.

  Natural antioxidants have recently emerged as a highly exciting and significant topic in anti-aging research. Diverse organism models present a viable protocol for future research. Notably, many breakthroughs on natural antioxidants have been achieved in the nematode Caenorhabditis elegans, an animal model frequently utilized for the study of aging research and anti-aging drugs in vivo. Due to the conservation of signaling pathways on oxidative stress resistance, lifespan regulation, and aging disease between C. elegans and multiple high-level organisms (humans), as well as the low and controllable cost of time and labor, it gradually develops into a trustworthy in vivo model for high-throughput screening and validation of natural antioxidants with anti-aging actions. First, information and models on free radicals and aging are presented in this review. We also describe indexes, detection methods, and molecular mechanisms for studying the in vivo antioxidant and anti-aging effects of natural antioxidants using C. elegans. It includes lifespan, physiological aging processes, oxidative stress levels, antioxidant enzyme activation, and anti-aging pathways. Furthermore, oxidative stress and healthspan improvement induced by natural antioxidants in humans and C. elegans are compared, to understand the potential and limitations of the screening model in preclinical studies. Finally, we emphasize that C. elegans is a useful model for exploring more natural antioxidant resources and uncovering the mechanisms underlying aging-related risk factors and diseases.

Keywords:  Anti-aging; Caenorhabditis elegans; High-throughput screening; Natural antioxidants; Oxidative stress

DOI:  https://doi.org/10.1016/j.biopha.2023.115594
Metabol Open. 2023 Dec;20 100257

Prevention of Alzheimer's disease through diet: An exploratory review.

Nusrat Zahan Bhuiyan, Md Kamrul Hasan, Zimam Mahmud, Md Sabbir Hossain, Atiqur Rahman.

   Introduction: This exploratory review article describes about the genetic factors behind Alzheimer's disease (AD), their association with foods, and their relationships with cognitive impairment. It explores the dietary patterns and economic challenges in AD prevention.
Methods: Scopus, PubMed and Google Scholar were searched for articles that examined the relationships between Diets, Alzheimer's Disease (AD), and Socioeconomic conditions in preventative Alzheimer's disease studies. Graphs and Network analysis data were taken from Scopus under the MeSH search method, including words, Alzheimer's, APoE4, Tau protein, APP, Amyloid precursor protein, Beta-Amyloid, Aβ, Mediterranean Diet, MD, DASH diet, MIND diet, SES, Socioeconomic, Developed country, Underdeveloped country, Preventions. The network analysis was done through VOS viewer.
Results: Mediterranean diet (MD) accurately lowers AD (Alzheimer's Disease) risk to 53% and 35% for people who follow it moderately. MIND scores had a statistically significant reduction in AD rate compared to those in the lowest tertial (53% and 35% reduction, respectively). Subjects with the highest adherence to the MD and DASH had a 54% and 39% lower risk of developing AD, respectively, compared to those in the lowest tertial. Omega-6, PUFA, found in nuts and fish, can play most roles in the clearance of Aβ. Vitamin D inhibits induced fibrillar Aβ apoptosis. However, the high cost of these diet components rise doubt about the effectiveness of AD prevention through healthy diets.
Conclusion: The finding of this study revealed an association between diet and the effects of the chemical components of foods on AD biomarkers. More research is required to see if nutrition is a risk or a protective factor for Alzheimer's disease to encourage research to be translated into therapeutic practice and to clarify nutritional advice.

Keywords:  AD biomarkers; Alzheimer's disease; DASH diet; Diets; MIND diet; Mediterranean diet

DOI:  https://doi.org/10.1016/j.metop.2023.100257
Curr Pain Headache Rep. 2023 Oct 04.

The Gut-brain Connection and Episodic Migraine: an Update.

Linda Nguyen, Nada Hindiyeh, Sutapa Ray, Robert E Vann, Sheena K Aurora.

   PURPOSE OF REVIEW: Historical evidence suggests a shared underlying etiology for migraine and gastrointestinal (GI) disorders that involves the gut-brain axis. Here we provide narrative review of recent literature on the gut-brain connection and migraine to emphasize the importance of tailoring treatment plans for patients with episodic migraine who experience GI comorbidities and symptoms.
RECENT FINDINGS: Recent population-based studies report the prevalence of migraine and GI disorders as comorbidities as well as overlapping symptomology. American Headache Society (AHS) guidelines have integrated GI symptoms as part of migraine diagnostic criteria and recommend nonoral therapies for patients with GI symptoms or conditions. Nasal delivery is a recommended nonoral alternative; however, it is important to understand potential adverse events that may cause or worsen GI symptoms in some patients due to the site of drug deposition within the nasal cavity with some nasal therapies. Lastly, clinical perspectives emphasize the importance of identifying GI symptoms and comorbidities in patients with episodic migraine to best individualize migraine management. Support for an association between the gut-brain axis and migraine continues to prevail in recent literature; however, the relationship remains complex and not well elucidated. The presence of GI comorbidities and symptoms must be carefully considered when making treatment decisions for patients with episodic migraine.

Keywords:  Episodic migraine; Gut-brain; Migraine

DOI:  https://doi.org/10.1007/s11916-023-01175-6
Elife. 2023 Oct 05. pii: e76465. [Epub ahead of print]12

Proteostasis is differentially modulated by inhibition of translation initiation or elongation.

Khalyd J Clay, Yongzhi Yang, Christina Clark, Michael Petrascheck.

  Recent work has revealed an increasingly important role for mRNA translation in maintaining proteostasis. Here, we use chemical inhibitors targeting discreet steps of translation to compare how lowering the concentration of all or only translation initiation-dependent proteins rescues Caenorhabditis elegans from proteotoxic stress. We systematically challenge proteostasis and show that pharmacologically inhibiting translation initiation or elongation elicits a distinct protective profile. Inhibiting elongation protects from heat and proteasome dysfunction independently from HSF-1 but does not protect from age-associated protein aggregation. Conversely, inhibition of initiation protects from heat and age-associated protein aggregation and increases lifespan, dependent on hsf-1, but does not protect from proteotoxicity caused by proteasome dysfunction. Surprisingly, we find that the ability of the translation initiation machinery to control the concentration of newly synthesized proteins depends on HSF-1. Inhibition of translation initiation in wild-type animals reduces the concentration of newly synthesized proteins but increases it in hsf-1 mutants. Our findings suggest that the HSF-1 pathway is not only a downstream target of translation but also directly cooperates with the translation initiation machinery to control the concentration of newly synthesized proteins to restore proteostasis.

Keywords:  C. elegans; biochemistry; cell biology; chemical biology

DOI:  https://doi.org/10.7554/eLife.76465
Neurotox Res. 2023 Sep 30.

RNA-Binding Proteins: A Role in Neurotoxicity?

Andrea Ocharán-Mercado, Jaqueline Loaeza-Loaeza, Yaneth Castro-Coronel, Leonor C Acosta-Saavedra, Luisa C Hernández-Kelly, Daniel Hernández-Sotelo, Arturo Ortega.

  Despite sustained efforts to treat neurodegenerative diseases, little is known at the molecular level to understand and generate novel therapeutic approaches for these malignancies. Therefore, it is not surprising that neurogenerative diseases are among the leading causes of death in the aged population. Neurons require sophisticated cellular mechanisms to maintain proper protein homeostasis. These cells are generally sensitive to loss of gene expression control at the post-transcriptional level. Post-translational control responds to signals that can arise from intracellular processes or environmental factors that can be regulated through RNA-binding proteins. These proteins recognize RNA through one or more RNA-binding domains and form ribonucleoproteins that are critically involved in the regulation of post-transcriptional processes from splicing to the regulation of association of the translation machinery allowing a relatively rapid and precise modulation of the transcriptome. Neurotoxicity is the result of the biological, chemical, or physical interaction of agents with an adverse effect on the structure and function of the central nervous system. The disruption of the proper levels or function of RBPs in neurons and glial cells triggers neurotoxic events that are linked to neurodegenerative diseases such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), fragile X syndrome (FXS), and frontotemporal dementia (FTD) among many others. The connection between RBPs and neurodegenerative diseases opens a new landscape for potentially novel therapeutic targets for the intervention of these neurodegenerative pathologies. In this contribution, a summary of the recent findings of the molecular mechanisms involved in the plausible role of RBPs in RNA processing in neurodegenerative disease is discussed.

Keywords:  Neurodegenerative diseases; Neurotoxicity; Post-transcriptional modifications; RNA-binding proteins

DOI:  https://doi.org/10.1007/s12640-023-00669-w