bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023–11–19
twelve papers selected by
Mikaila Chetty, Goa University
  1. Understanding the Gut-Brain Axis and Its Therapeutic Implications for Neurodegenerative Disorders.
  2. Common and Trace Metals in Alzheimer's and Parkinson's Diseases.
  3. Neuronanomedicine for Alzheimer's and Parkinson's disease: Current progress and a guide to improve clinical translation.
  4. Multifunctional Nanocarriers for Alzheimer's Disease: Befriending the Barriers.
  5. The Role of mRNA Quality Control in the Aging of Caenorhabditis elegans.
  6. Antibiotics that target mitochondria extend lifespan in C. elegans.
  7. The role of nutrition and oxidative stress as aging factors in Caenorhabditis elegans.
  8. Role and molecular regulatory mechanisms of Hippo signaling pathway in Caenorhabditis elegans and mammalian cell models of Alzheimer's disease.
  9. Cadmium-induced reproductive toxicity combined with a correlation to the oogenesis process and competing endogenous RNA networks based on a Caenorhabditis elegans model.
  10. Specific sensory neurons and insulin-like peptides modulate food type-dependent oogenesis and fertilization in Caenorhabditis elegans.
  11. Gut inflammation associated with age and Alzheimer's disease pathology: a human cohort study.
  12. Silicon-Carbon Dots-Loaded Mesoporous Silica Nanocomposites (mSiO2@SiCDs): An Efficient Dual Inhibitor of Cu2+-Mediated Oxidative Stress and Aβ Aggregation for Alzheimer's Disease.
  1. Nutrients. 2023 Oct 31. pii: 4631. [Epub ahead of print]15(21):
    Understanding the Gut-Brain Axis and Its Therapeutic Implications for Neurodegenerative Disorders.
    Yadong Zheng, Laura Bonfili, Tao Wei, Anna Maria Eleuteri.
      The gut-brain axis (GBA) is a complex bidirectional communication network connecting the gut and brain. It involves neural, immune, and endocrine communication pathways between the gastrointestinal (GI) tract and the central nervous system (CNS). Perturbations of the GBA have been reported in many neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), among others, suggesting a possible role in disease pathogenesis. The gut microbiota is a pivotal component of the GBA, and alterations in its composition, known as gut dysbiosis, have been associated with GBA dysfunction and neurodegeneration. The gut microbiota might influence the homeostasis of the CNS by modulating the immune system and, more directly, regulating the production of molecules and metabolites that influence the nervous and endocrine systems, making it a potential therapeutic target. Preclinical trials manipulating microbial composition through dietary intervention, probiotic and prebiotic supplementation, and fecal microbial transplantation (FMT) have provided promising outcomes. However, its clear mechanism is not well understood, and the results are not always consistent. Here, we provide an overview of the major components and communication pathways of the GBA, as well as therapeutic approaches targeting the GBA to ameliorate NDDs.
    Keywords:  gut dysbiosis; gut microbiota; gut–brain axis; neurodegenerative disorders; probiotics
    DOI:  https://doi.org/10.3390/nu15214631
  2. Int J Mol Sci. 2023 Oct 29. pii: 15721. [Epub ahead of print]24(21):
    Common and Trace Metals in Alzheimer's and Parkinson's Diseases.
    Julia Doroszkiewicz, Jakub Ali Farhan, Jan Mroczko, Izabela Winkel, Maciej Perkowski, Barbara Mroczko.
      Trace elements and metals play critical roles in the normal functioning of the central nervous system (CNS), and their dysregulation has been implicated in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). In a healthy CNS, zinc, copper, iron, and manganese play vital roles as enzyme cofactors, supporting neurotransmission, cellular metabolism, and antioxidant defense. Imbalances in these trace elements can lead to oxidative stress, protein aggregation, and mitochondrial dysfunction, thereby contributing to neurodegeneration. In AD, copper and zinc imbalances are associated with amyloid-beta and tau pathology, impacting cognitive function. PD involves the disruption of iron and manganese levels, leading to oxidative damage and neuronal loss. Toxic metals, like lead and cadmium, impair synaptic transmission and exacerbate neuroinflammation, impacting CNS health. The role of aluminum in AD neurofibrillary tangle formation has also been noted. Understanding the roles of these elements in CNS health and disease might offer potential therapeutic targets for neurodegenerative disorders. The Codex Alimentarius standards concerning the mentioned metals in foods may be one of the key legal contributions to safeguarding public health. Further research is needed to fully comprehend these complex mechanisms and develop effective interventions.
    Keywords:  Codex Alimentarius; diet; food; heavy metals; neurodegeneration; trace elements
    DOI:  https://doi.org/10.3390/ijms242115721
  3. Brain Behav Immun. 2023 Nov 13. pii: S0889-1591(23)00337-9. [Epub ahead of print]
    Neuronanomedicine for Alzheimer's and Parkinson's disease: Current progress and a guide to improve clinical translation.
    India Boyton, Stella M Valenzuela, Lyndsey E Collins-Praino, Andrew Care.
      Neuronanomedicine is an emerging multidisciplinary field that aims to create innovative nanotechnologies to treat major neurodegenerative disorders, such as Alzheimer's (AD) and Parkinson's disease (PD). A key component of neuronanomedicine are nanoparticles, which can improve drug properties and demonstrate enhanced safety and delivery across the blood brain barrier, a major improvement on existing therapeutic approaches. In this review, we critically analyze the latest nanoparticle-based strategies to modify underlying disease pathology to slow or halt AD/PD progression. We find that a major roadblock for neuronanomedicine translation to date is a poor understanding of how nanoparticles interact with biological systems (i.e., bio-nano interactions), which is partly due to inconsistent reporting in published works. Accordingly, this review makes a set of specific recommendations to help guide researchers to harness the unique properties of nanoparticles and thus realise breakthrough treatments for AD/PD.
    Keywords:  Alzheimer’s disease; Drug delivery; Nanomedicine; Nanoparticle-based drug delivery systems; Nanoparticles; Neurodegeneration; Parkinsonism
    DOI:  https://doi.org/10.1016/j.bbi.2023.11.004
  4. Mol Neurobiol. 2023 Nov 15.
    Multifunctional Nanocarriers for Alzheimer's Disease: Befriending the Barriers.
    Mohammad Azam Ansari, Takshashila Tripathi, Baskar Venkidasamy, Alan Monziani, Govindasamy Rajakumar, Mohammad N Alomary, Sami A Alyahya, Oriane Onimus, Naomi D'souza, Md Abul Barkat, Ebtesam A Al-Suhaimi, Ramkumar Samynathan, Muthu Thiruvengadam.
      Neurodegenerative diseases (NDDs) have been increasing in incidence in recent years and are now widespread worldwide. Neuronal death is defined as the progressive loss of neuronal structure or function which is closely associated with NDDs and represents the intrinsic features of such disorders. Amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's, Parkinson's, and Huntington's diseases (AD, PD, and HD, respectively) are considered neurodegenerative diseases that affect a large number of people worldwide. Despite the testing of various drugs, there is currently no available therapy that can remedy or effectively slow the progression of these diseases. Nanomedicine has the potential to revolutionize drug delivery for the management of NDDs. The use of nanoparticles (NPs) has recently been developed to improve drug delivery efficiency and is currently subjected to extensive studies. Nanoengineered particles, known as nanodrugs, can cross the blood-brain barrier while also being less invasive compared to the most treatment strategies in use. Polymeric, magnetic, carbonic, and inorganic NPs are examples of NPs that have been developed to improve drug delivery efficiency. Primary research studies using NPs to cure AD are promising, but thorough research is needed to introduce these approaches to clinical use. In the present review, we discussed the role of metal-based NPs, polymeric nanogels, nanocarrier systems such as liposomes, solid lipid NPs, polymeric NPs, exosomes, quantum dots, dendrimers, polymersomes, carbon nanotubes, and nanofibers and surfactant-based systems for the therapy of neurodegenerative diseases. In addition, we highlighted nanoformulations such as N-butyl cyanoacrylate, poly(butyl cyanoacrylate), D-penicillamine, citrate-coated peptide, magnetic iron oxide, chitosan (CS), lipoprotein, ceria, silica, metallic nanoparticles, cholinesterase inhibitors, an acetylcholinesterase inhibitors, metal chelators, anti-amyloid, protein, and peptide-loaded NPs for the treatment of AD.
    Keywords:  Alzheimer’s disease; Blood–brain barrier; Nanocarriers; Nanoformulation; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12035-023-03730-z
  5. Mol Cells. 2023 Nov 30. 46(11): 664-671
    The Role of mRNA Quality Control in the Aging of Caenorhabditis elegans.
    Hyunwoo C Kwon, Yunkyu Bae, Seung-Jae V Lee.
      The proper maintenance of mRNA quality that is regulated by diverse surveillance pathways is essential for cellular homeostasis and is highly conserved among eukaryotes. Here, we review findings regarding the role of mRNA quality control in the aging and longevity of Caenorhabditis elegans, an outstanding model for aging research. We discuss the recently discovered functions of the proper regulation of nonsense-mediated mRNA decay, ribosome-associated quality control, and mRNA splicing in the aging of C. elegans. We describe how mRNA quality control contributes to longevity conferred by various regimens, including inhibition of insulin/insulin-like growth factor 1 (IGF-1) signaling, dietary restriction, and reduced mechanistic target of rapamycin signaling. This review provides valuable information regarding the relationship between the mRNA quality control and aging in C. elegans, which may lead to insights into healthy longevity in complex organisms, including humans.
    Keywords:  Caenorhabditis elegans; aging; alternative splicing; mRNA surveillance; nonsense-mediated mRNA decay; ribosome-associated quality control
    DOI:  https://doi.org/10.14348/molcells.2023.0103
  6. Aging (Albany NY). 2023 Nov 09. 15
    Antibiotics that target mitochondria extend lifespan in C. elegans.
    Gloria Bonuccelli, Darren R Brooks, Sally Shepherd, Federica Sotgia, Michael P Lisanti.
      Aging is a continuous degenerative process caused by a progressive decline of cell and tissue functions in an organism. It is induced by the accumulation of damage that affects normal cellular processes, ultimately leading to cell death. It has been speculated for many years that mitochondria play a key role in the aging process. In the aim of characterizing the implications of mitochondria in aging, here we used Caenorhabditis elegans (C. elegans) as an organismal model treated a panel of mitochondrial inhibitors and assessed for survival. In our study, we assessed survival by evaluating worm lifespan, and we assessed aging markers by evaluating the pharyngeal muscle contraction, the accumulation of lipofuscin pigment and ATP levels. Our results show that treatment of worms with either doxycycline, azithromycin (inhibitors of the small and the large mitochondrial ribosomes, respectively), or a combination of both, significantly extended median lifespan of C. elegans, enhanced their pharyngeal pumping rate, reduced their lipofuscin content and their energy consumption (ATP levels), as compared to control untreated worms, suggesting an aging-abrogating effect for these drugs. Similarly, DPI, an inhibitor of mitochondrial complex I and II, was capable of prolonging the median lifespan of treated worms. On the other hand, subjecting worms to vitamin C, a pro-oxidant, failed to extend C. elegans lifespan and upregulated its energy consumption, revealing an increase in ATP level. Therefore, our longevity study reveals that mitochondrial inhibitors (i.e., mitochondria-targeting antibiotics) could abrogate aging and extend lifespan in C. elegans.
    Keywords:  C. elegans; DPI; aging; antibiotics; lifespan; lipofuscin; metabolism; mitochondria
    DOI:  https://doi.org/10.18632/aging.205229
  7. J Clin Biochem Nutr. 2023 Nov;73(3): 173-177
    The role of nutrition and oxidative stress as aging factors in Caenorhabditis elegans.
    Kayo Yasuda, Masaki Miyazawa, Takamasa Ishii, Naoaki Ishii.
      The molecular mechanism of aging, which has been a "black box" for many years, has been elucidated in recent years, and the nematode C. elegans, which is a model animal for aging research, has played a major role in its elucidation. From the analysis of C. elegans longevity-related mutant genes, many signal transduction systems, with the insulin/insulin-like growth factor signal transduction system at the core, have emerged. It has become clear that this signal transduction system is greatly affected by external nutrients and is involved in the downstream regulation of oxidative stress, which is considered to be one of the main causes of aging.
    Keywords:  Caenorhabditis elegans; aging; nutrition; oxidative stress
    DOI:  https://doi.org/10.3164/jcbn.23-44
  8. Neurobiol Aging. 2023 Sep 28. pii: S0197-4580(23)00233-6. [Epub ahead of print]134 9-20
    Role and molecular regulatory mechanisms of Hippo signaling pathway in Caenorhabditis elegans and mammalian cell models of Alzheimer's disease.
    Man Zhu, Huan Gu, Hua Bai, Yixin Li, Chidi Zhong, Xiaowei Huang.
      Although there is increasing evidence for the involvement of Hippo signaling in Alzheimer's disease (AD), the detailed functions and regulatory mechanisms are not fully understood, given the diverse biological effects of this pathway. In the present work, we used Caenorhabditis elegans and mammalian cell models to investigate changes in the Hippo signaling pathway in response to Aβ and the downstream effects on AD development. Aβ1-42 production in the AD models decreased phosphorylation of the upstream CST-1/WTS-1 kinase cascade and promoted an interaction between LIN-10 and YAP-1, leading to the nuclear translocation of YAP-1 and inducing gene transcription in conjunction with the transcription factor EGL-44. The YAP-1/EGL-44 complex suppressed the autophagy-lysosome pathway by modulating mTOR signaling, which enhanced Aβ1-42 accumulation and promoted AD progression. These results demonstrate for the first time that crosstalk between Hippo and mTOR signaling contributes to AD development by enhancing Aβ production, resulting in inhibition of Hippo signaling and autophagy-lysosome pathway and Aβ accumulation, suggesting potential therapeutic targets for the treatment or prevention of AD.
    Keywords:  Alzheimer’s disease; Autophagy-lysosome pathway; Caenorhabditis elegans; Hippo pathway; LIN-10
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2023.09.015
  9. Ecotoxicol Environ Saf. 2023 Nov 15. pii: S0147-6513(23)01191-0. [Epub ahead of print]268 115687
    Cadmium-induced reproductive toxicity combined with a correlation to the oogenesis process and competing endogenous RNA networks based on a Caenorhabditis elegans model.
    Zhi Qu, Limin Liu, Xiaoliang Wu, Peisen Guo, Zengli Yu, Peixi Wang, Yuzhen Song, Shanqing Zheng, Nan Liu.
      Accumulation of the heavy metal Cadmium (Cd) in the ovaries and placenta can affect the structure and function of these organs and induce female reproductive toxicity. This toxicity may be due to Cd's similarity to estrogen and its ability to disrupt endocrine systems. However, the exact molecular mechanism by which Cd causes reproductive toxicity at the transcriptome level remains poorly understood. Hence, this study aimed to observe Cd-induced reproductive damage at the gene level, scrutinize the repercussions of Cd exposure on oogenesis, and explicate the putative pathogenesis of Cd-induced oogenesis based on Caenorhabditis elegans (C. elegans) as an in vivo model. The results showed that Cd exposure significantly decreased the number of offspring and prolonged the reproductive span of C. elegans. Cd exposure also reduced the number of cells in mitosis and the pachytene and diakinesis stages of meiosis, thereby disrupting oogenesis. Combined with transcriptional sequencing and bioinformatics analysis, a total of 3167 DEmRNAs were identified. Regarding gene expression, cul-6, mum-2, and vang-1 were found to be related to Cd-induced reproductive toxicity, and their competing endogenous RNA networks were constructed. We observed that mutations of mom-2 and vang-1 in the Wnt pathway could induce susceptibility to Cd-caused meiosis injury. In conclusion, the results indicated that Cd could impair the oogenesis of C. elegans and the Wnt pathway might serve as a protective mechanism against Cd reproductive toxicity. These findings contribute to a better understanding of the damaging effects and molecular biological mechanisms of Cd on the human reproductive system.
    Keywords:  Cadmium exposure; Caenorhabditis elegans; CeRNA network; Reproductive toxicity; Transcriptomics
    DOI:  https://doi.org/10.1016/j.ecoenv.2023.115687
  10. Elife. 2023 Nov 17. pii: e83224. [Epub ahead of print]12
    Specific sensory neurons and insulin-like peptides modulate food type-dependent oogenesis and fertilization in Caenorhabditis elegans.
    Shashwat Mishra, Mohamed Dabaja, Asra Akhlaq, Bianca Pereira, Kelsey Marbach, Mediha Rovcanin, Rashmi Chandra, Antonio Caballero, Diana Fernandes de Abreu, QueeLim Ch'ng, Joy Alcedo.
      An animal's responses to environmental cues are critical for its reproductive program. Thus, a mechanism that allows the animal to sense and adjust to its environment should make for a more efficient reproductive physiology. Here we demonstrate that in Caenorhabditis elegans specific sensory neurons influence onset of oogenesis through insulin signaling in response to food-derived cues. The chemosensory neurons ASJ modulate oogenesis onset through the insulin-like peptide (ILP) INS‑6. In contrast, other sensory neurons, the olfactory neurons AWA, regulate food type-dependent differences in C. elegans fertilization rates, but not onset of oogenesis. AWA modulates fertilization rates at least partly in parallel to insulin receptor signaling, since the insulin receptor DAF‑2 regulates fertilization independently of food type, which requires ILPs other than INS-6. Together our findings suggest that optimal reproduction requires the integration of diverse food-derived inputs through multiple neuronal signals acting on the C. elegans germline.
    Keywords:  C. elegans; cell biology; developmental biology
    DOI:  https://doi.org/10.7554/eLife.83224
  11. Sci Rep. 2023 Nov 14. 13(1): 18924
    Gut inflammation associated with age and Alzheimer's disease pathology: a human cohort study.
    Margo B Heston, Kendra L Hanslik, Katie R Zarbock, Sandra J Harding, Nancy J Davenport-Sis, Robert L Kerby, Nathaniel Chin, Yi Sun, Ana Hoeft, Yuetiva Deming, Nicholas M Vogt, Tobey J Betthauser, Sterling C Johnson, Sanjay Asthana, Gwendlyn Kollmorgen, Ivonne Suridjan, Norbert Wild, Henrik Zetterberg, Kaj Blennow, Federico E Rey, Barbara B Bendlin, Tyler K Ulland.
      Age-related disease may be mediated by low levels of chronic inflammation ("inflammaging"). Recent work suggests that gut microbes can contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer's disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation remains unclear. To investigate whether greater gut inflammation is associated with advanced age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity. Multiple regression with maximum likelihood estimation and Satorra-Bentler corrections were used to test relationships between fecal calprotectin and clinical diagnosis, participant age, cerebrospinal fluid biomarkers of AD pathology, amyloid burden measured using 11C-Pittsburgh compound B positron emission tomography (PiB PET) imaging, and performance on cognitive tests measuring executive function and verbal learning and recall. Calprotectin levels were elevated in advanced age and were higher in participants diagnosed with amyloid-confirmed AD dementia. Additionally, among individuals with AD dementia, higher calprotectin was associated with greater amyloid burden as measured with PiB PET. Exploratory analyses indicated that calprotectin levels were also associated with cerebrospinal fluid markers of AD, and with lower verbal memory function even among cognitively unimpaired participants. Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD.
    DOI:  https://doi.org/10.1038/s41598-023-45929-z
  12. ACS Appl Mater Interfaces. 2023 Nov 14.
    Silicon-Carbon Dots-Loaded Mesoporous Silica Nanocomposites (mSiO2@SiCDs): An Efficient Dual Inhibitor of Cu2+-Mediated Oxidative Stress and Aβ Aggregation for Alzheimer's Disease.
    Qin-Ying Li, Xu Yu, Xi Li, Li-Na Bao, Yu Zhang, Min-Jie Xie, Ming Jiang, Ya Qian Wang, Kun Huang, Li Xu.
      The redox-active metal ions, especially Cu2+, are highly correlated to Alzheimer's disease (AD) by causing metal ion-mediated oxidative stress and toxic metal-bound β-amyloid (Aβ) aggregates. Numerous pieces of evidence have revealed that the regulation of metal homeostasis could be an effective therapeutic strategy for AD. Herein, in virtue of the interaction of both amino-containing silane and ethylenediaminetetraacetic acid disodium salt for Cu2+, the silicon-carbon dots (SiCDs) are deliberately prepared using these two raw materials as the cocarbon source; meanwhile, to realize the local enrichment of SiCDs and further maximize the chelating ability to Cu2+, the SiCDs are feasibly loaded to the biocompatible mesoporous silica nanoparticles (mSiO2) with the interaction between residual silane groups on SiCDs and silanol groups of mSiO2. Thus-obtained nanocomposites (i.e., mSiO2@SiCDs) could serve as an efficient Cu2+ chelator with satisfactory metal selectivity and further modulate the enzymic activity of free Cu2+ and the Aβ42-Cu2+ complex to alleviate the pathological oxidative stress with an anti-inflammatory effect. Besides, mSiO2@SiCDs show an inspiring inhibitory effect on Cu2+-mediated Aβ aggregation and further protect the neural cells against the toxic Aβ42-Cu2+ complex. Moreover, the transgenic Caenorhabditis elegans CL2120 assay demonstrates the protective efficacy of mSiO2@SiCDs on Cu2+-mediated Aβ toxicity in vivo, indicating its potential for AD treatment.
    Keywords:  Alzheimer’s disease; Cu2+ chelation; mesoporous silica nanoparticles; silicon–carbon dots; β-amyloid
    DOI:  https://doi.org/10.1021/acsami.3c10053
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