bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2024‒01‒07
six papers selected by
Mikaila Chetty, Goa University
  1. Assessing locomotory rate in response to food for the identification of neuronal and muscular defects in C. elegans.
  2. The consequence of ATP synthase dimer angle on mitochondrial morphology studied by cryo-electron tomography.
  3. Exploring novel experimental treatments for major neurodegenerative disorders.
  4. Copper and cuproptosis: new therapeutic approaches for Alzheimer's disease.
  5. Amyloid Targeting Red Emitting AIE Dots for Diagnostic and Therapeutic Application against Alzheimer's Disease.
  6. Palmitic Acid Induces Posttranslational Modifications of Tau Protein in Alzheimer's Disease-Related Epitopes and Increases Intraneuronal Tau Levels.
  1. STAR Protoc. 2023 Dec 29. pii: S2666-1667(23)00768-2. [Epub ahead of print]5(1): 102801
    Assessing locomotory rate in response to food for the identification of neuronal and muscular defects in C. elegans.
    Dionysia Petratou, Persefoni Fragkiadaki, Eirini Lionaki, Nektarios Tavernarakis.
      C. elegans is a bacteria-eating soil-dwelling nematode. Typical cultivation of laboratory-reared populations occurs on bacteria-covered solid media, where they move along with sinusoidal undulations. Nematodes decelerate when they encounter food. Dopaminergic and serotonergic neurotransmission regulate this behavior. Here, we describe the procedure for determining food-dependent locomotion rate of fed and fasting nematodes. We detail steps for assay plate preparation, C. elegans synchronization, and assessment of locomotion. The behaviors we describe provide information regarding the animal's physiological neuronal and muscular function. For complete details on the use and execution of this protocol, please refer to Petratou et al. (2023)1 and Sawin et al. (2000).2.
    Keywords:  Behavior; Genetics; Microscopy; Model Organisms; Signal Transduction
    DOI:  https://doi.org/10.1016/j.xpro.2023.102801
  2. Biochem J. 2024 Jan 02. pii: BCJ20230450. [Epub ahead of print]
    The consequence of ATP synthase dimer angle on mitochondrial morphology studied by cryo-electron tomography.
    Emma Buzzard, Mathew McLaren, Piotr Bragoszewski, Andrea Brancaccio, Holly Ford, Bertram Daum, Patricia Kuwabara, Ian Collinson, Vicki Gold.
      Mitochondrial ATP synthases form rows of dimers, which induce membrane curvature to give cristae their characteristic lamellar or tubular morphology. The angle formed between the central stalks of ATP synthase dimers varies between species. Using cryo-electron tomography and sub-tomogram averaging, we determined the structure of the ATP synthase dimer from the nematode worm C. elegans and show that the dimer angle differs from previously determined structures. The consequences of this species-specific difference at the dimer interface were investigated by comparing C. elegans and S. cerevisiae mitochondrial morphology. We reveal that C. elegans has a larger ATP synthase dimer angle with more lamellar (flatter) cristae when compared to yeast. The underlying cause of this difference was investigated by generating an atomic model of the C. elegans ATP synthase dimer by homology modelling. A comparison of our C. elegans model to an existing S. cerevisiae structure reveals the presence of extensions and rearrangements in C. elegans subunits associated with maintaining the dimer interface. We speculate that increasing dimer angles could provide an advantage for species that inhabit variable-oxygen environments by forming flatter more energetically efficient cristae.
    Keywords:  alphafold; atp synthase; cryo-electron microscopy; mitochondria; sub-tomogram averaging
    DOI:  https://doi.org/10.1042/BCJ20230450
  3. Neuroprotection. 2023 Dec;1(2): 81-83
    Exploring novel experimental treatments for major neurodegenerative disorders.
    Xunming Ji, Piotr Walczak, Johannes Boltze.
      
    Keywords:  Alzheimer's disease; amyotrophic lateral sclerosis; cell therapy; cytoprotection; extracellular vesicles; neurodegeneration; stroke
    DOI:  https://doi.org/10.1002/nep3.31
  4. Front Aging Neurosci. 2023 ;15 1300405
    Copper and cuproptosis: new therapeutic approaches for Alzheimer's disease.
    Xiao Li, Xinwang Chen, Xiyan Gao.
      Copper (Cu) plays a crucial role as a trace element in various physiological processes in humans. Nonetheless, free copper ions accumulate in the brain over time, resulting in a range of pathological changes. Compelling evidence indicates that excessive free copper deposition contributes to cognitive decline in individuals with Alzheimer's disease (AD). Free copper levels in the serum and brain of AD patients are notably elevated, leading to reduced antioxidant defenses and mitochondrial dysfunction. Moreover, free copper accumulation triggers a specific form of cell death, namely copper-dependent cell death (cuproptosis). This article aimed to review the correlation between copper dysregulation and the pathogenesis of AD, along with the primary pathways regulating copper homoeostasis and copper-induced death in AD. Additionally, the efficacy and safety of natural and synthetic agents, including copper chelators, lipid peroxidation inhibitors, and antioxidants, were examined. These treatments can restore copper equilibrium and prevent copper-induced cell death in AD cases. Another aim of this review was to highlight the significance of copper dysregulation and promote the development of pharmaceutical interventions to address it.
    Keywords:  Alzheimer’s disease; chelators; copper; cuproptosis; long-term potentiation
    DOI:  https://doi.org/10.3389/fnagi.2023.1300405
  5. ACS Chem Neurosci. 2024 Jan 03.
    Amyloid Targeting Red Emitting AIE Dots for Diagnostic and Therapeutic Application against Alzheimer's Disease.
    Priyam Ghosh, Kamal Shokeen, Subrata Mondal, Thirukumaran Kandasamy, Sachin Kumar, Siddhartha Sankar Ghosh, Parameswar Krishnan Iyer.
      The emergence of neurodegenerative diseases is connected to several pathogenic factors, including metal ions, amyloidogenic proteins, and reactive oxygen species. Recent studies suggest that cytotoxicity is caused by the small, dynamic, and metastable nature of early stage oligomeric species. This work introduces a small molecule-based red-emitting probe with smart features such as increased reactivities against multiple targets, metal-free amyloid-β (Aβ), and metal-bound amyloid-β (Aβ), and most importantly, early stage oligomeric species which are associated with the most common and widespread type of dementia, Alzheimer's disease (AD). Theoretical analyses like molecular dynamics simulation and molecular docking were performed to confirm the reactivity of the molecule toward Aβ and found some excellent interactions between the molecule and the peptide. The in vitro and cellular studies demonstrated that this highly biocompatible molecule effectively reduces the structural damage to mitochondria while shielding cells from apoptosis, scavenges ROS (reactive oxygen species), and attenuates multifaceted amyloid toxicity.
    Keywords:  AIE dots; Alzheimer’s disease; Amyloid oligomer; copper chelation; mitochondrial damage; neurotoxicity; red emitting
    DOI:  https://doi.org/10.1021/acschemneuro.3c00473
  6. Mol Neurobiol. 2024 Jan 03.
    Palmitic Acid Induces Posttranslational Modifications of Tau Protein in Alzheimer's Disease-Related Epitopes and Increases Intraneuronal Tau Levels.
    Valeria Melissa García-Cruz, Clorinda Arias.
      Metabolic diseases derived from an unhealthy lifestyle have been linked with an increased risk for developing cognitive impairment and even Alzheimer's disease (AD). Although high consumption of saturated fatty acids such as palmitic acid (PA) has been associated with the development of obesity and type II diabetes, the mechanisms connecting elevated neuronal PA levels and increased AD marker expression remain unclear. Among other effects, PA induces insulin resistance, increases intracellular calcium and reactive oxygen species (ROS) production, and reduces the NAD+/NADH ratio, resulting in decreased activity of the deacetylase Sirtuin1 (SIRT1) in neurons. These mechanisms may affect signaling pathways that impact the posttranslational modifications (PTMs) of the tau protein. To analyze the role played by PA in inducing the phosphorylation and acetylation of tau, we examined PTM changes in human tau in differentiated neurons from human neuroblastoma cells. We found changes in the phosphorylation state of several AD-related sites, namely, S199/202 and S214, that were mediated by a mechanism associated with the dysregulated activity of the kinases GSK3β and mTOR. PA also increased the acetylation of residue K280 and elevated total tau level after long exposure time. These findings provide information about the mechanisms by which saturated fatty acids cause tau PTMs that are similar to those observed in association with AD biochemical changes.
    Keywords:  GSK3β; PP2A; Palmitic acid; Tau acetylation; Tau phosphorylation; mTORC1
    DOI:  https://doi.org/10.1007/s12035-023-03886-8
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