bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023–11–26
seven papers selected by
Mikaila Chetty, Goa University
  1. Intracerebral Nanoparticle Transport Facilitated by Alzheimer Pathology and Age.
  2. PHYTOMOLECULES FROM CONVENTIONAL TO NANO FORM: NEXT-GENERATION APPROACH FOR PARKINSON'S DISEASE.
  3. Mitochondrial DNA and Inflammation in Alzheimer's Disease.
  4. Tryptophan Metabolism and Gut Microbiota: A Novel Regulatory Axis Integrating the Microbiome, Immunity, and Cancer.
  5. Oxidative Stress in Health and Disease.
  6. The Protective Effects of Reineckia carnea Ether Fraction against Alzheimer's Disease Pathology: An Exploration in Caenorhabditis elegans Models.
  7. Early-life caffeine exposure induces morphological changes and altered physiology in Caenorhabditiselegans.
  1. Nano Lett. 2023 Nov 22.
    Intracerebral Nanoparticle Transport Facilitated by Alzheimer Pathology and Age.
    Gregory C Tracy, Kai-Yu Huang, Yu-Tong Hong, Shengzhe Ding, Hayden A Noblet, Ki H Lim, Eung Chang Kim, Hee Jung Chung, Hyunjoon Kong.
      Nanoparticles have emerged as potential transporters of drugs targeting Alzheimer's disease (AD), but their design should consider the blood-brain barrier (BBB) integrity and neuroinflammation of the AD brain. This study presents that aging is a significant factor for the brain localization and retention of nanoparticles, which we engineered to bind with reactive astrocytes and activated microglia. We assembled 200 nm-diameter particles using a block copolymer of poly(lactic-co-glycolic acid) (PLGA) and CD44-binding hyaluronic acid (HA). The resulting PLGA-b-HA nanoparticles displayed increased binding to CD44-expressing reactive astrocytes and activated microglia. Upon intravascular injection, nanoparticles were localized to the hippocampi of both APP/PS1 AD model mice and their control littermates at 13-16 months of age due to enhanced transvascular transport through the leaky BBB. No particles were found in the hippocampi of young adult mice. These findings demonstrate the brain localization of nanoparticles due to aging-induced BBB breakdown regardless of AD pathology.
    Keywords:  Alzheimer’s disease; PLGA nanoparticles; aging; blood-brain barrier; hyaluronic acid; reactive astrocytes
    DOI:  https://doi.org/10.1021/acs.nanolett.3c03222
  2. Ageing Res Rev. 2023 Nov 22. pii: S1568-1637(23)00295-7. [Epub ahead of print] 102136
    PHYTOMOLECULES FROM CONVENTIONAL TO NANO FORM: NEXT-GENERATION APPROACH FOR PARKINSON'S DISEASE.
    Sweta Priyadarshini Pradhan, P Tejaswani, Anindita Behera, Pratap Kumar Sahu.
      The incidence of neurodegenerative diseases is increasing exponentially worldwide. Parkinson's disease (PD) is a neurodegenerative disease caused by factors like oxidative stress, gene mutation, mitochondrial dysfunction, neurotoxins, activation of microglial inflammatory mediators, deposition of Lewy's bodies, and α- synuclein proteins in the neurons leading to neuroinflammation and neurodegeneration in the substantia nigra. Hence the development of efficacious neuro-therapy is in demand which can prevent neurodegeneration and protect the nigrostriatal pathway. One of the approaches for managing PD is reducing oxidative stress due to aging and other co-morbid diseased conditions. The phytomolecules are reported as safe and efficacious antioxidants as they contain different secondary metabolites. However, the limitations of low solubility restricted permeability through the blood-brain barrier, and low bioavailability limits their clinical evaluation and application. This review discusses the therapeutic efficacy of phytomolecules in PD and different nanotechnological approaches to improve their brain permeability.
    Keywords:  Parkinson’s disease; nanotechnology; neurodegeneration; oxidative stress; phytomolecules
    DOI:  https://doi.org/10.1016/j.arr.2023.102136
  3. Curr Issues Mol Biol. 2023 Oct 25. 45(11): 8586-8606
    Mitochondrial DNA and Inflammation in Alzheimer's Disease.
    Giacoma Galizzi, Marta Di Carlo.
      Mitochondrial dysfunction and neuroinflammation are implicated in the pathogenesis of most neurodegenerative diseases, such as Alzheimer's disease (AD). In fact, although a growing number of studies show crosstalk between these two processes, there remain numerous gaps in our knowledge of the mechanisms involved, which requires further clarification. On the one hand, mitochondrial dysfunction may lead to the release of mitochondrial damage-associated molecular patterns (mtDAMPs) which are recognized by microglial immune receptors and contribute to neuroinflammation progression. On the other hand, inflammatory molecules released by glial cells can influence and regulate mitochondrial function. A deeper understanding of these mechanisms may help identify biomarkers and molecular targets useful for the treatment of neurodegenerative diseases. This review of works published in recent years is focused on the description of the mitochondrial contribution to neuroinflammation and neurodegeneration, with particular attention to mitochondrial DNA (mtDNA) and AD.
    Keywords:  Alzheimer’s disease; DAMPs; glia; microglia; mitochondria; mitochondrial dysfunction; mtDNA; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.3390/cimb45110540
  4. Metabolites. 2023 Nov 20. pii: 1166. [Epub ahead of print]13(11):
    Tryptophan Metabolism and Gut Microbiota: A Novel Regulatory Axis Integrating the Microbiome, Immunity, and Cancer.
    Yingjian Hou, Jing Li, Shuhuan Ying.
      Tryptophan metabolism and gut microbiota form an integrated regulatory axis that impacts immunity, metabolism, and cancer. This review consolidated current knowledge on the bidirectional interactions between microbial tryptophan processing and the host. We focused on how the gut microbiome controls tryptophan breakdown via the indole, kynurenine, and serotonin pathways. Dysbiosis of the gut microbiota induces disruptions in tryptophan catabolism which contribute to disorders like inflammatory conditions, neuropsychiatric diseases, metabolic syndromes, and cancer. These disruptions affect immune homeostasis, neurotransmission, and gut-brain communication. Elucidating the mechanisms of microbial tryptophan modulation could enable novel therapeutic approaches like psychobiotics and microbiome-targeted dietary interventions. Overall, further research on the microbiota-tryptophan axis has the potential to revolutionize personalized diagnostics and treatments for improving human health.
    Keywords:  immune balance; kynurenine pathway; microbiota; tryptophan
    DOI:  https://doi.org/10.3390/metabo13111166
  5. Biomedicines. 2023 Oct 29. pii: 2925. [Epub ahead of print]11(11):
    Oxidative Stress in Health and Disease.
    V Prakash Reddy.
      Oxidative stress, resulting from the excessive intracellular accumulation of reactive oxygen species (ROS), reactive nitrogen species (RNS), and other free radical species, contributes to the onset and progression of various diseases, including diabetes, obesity, diabetic nephropathy, diabetic neuropathy, and neurological diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Oxidative stress is also implicated in cardiovascular disease and cancer. Exacerbated oxidative stress leads to the accelerated formation of advanced glycation end products (AGEs), a complex mixture of crosslinked proteins and protein modifications. Relatively high levels of AGEs are generated in diabetes, obesity, AD, and other I neurological diseases. AGEs such as Ne-carboxymethyllysine (CML) serve as markers for disease progression. AGEs, through interaction with receptors for advanced glycation end products (RAGE), initiate a cascade of deleterious signaling events to form inflammatory cytokines, and thereby further exacerbate oxidative stress in a vicious cycle. AGE inhibitors, AGE breakers, and RAGE inhibitors are therefore potential therapeutic agents for multiple diseases, including diabetes and AD. The complexity of the AGEs and the lack of well-established mechanisms for AGE formation are largely responsible for the lack of effective therapeutics targeting oxidative stress and AGE-related diseases. This review addresses the role of oxidative stress in the pathogenesis of AGE-related chronic diseases, including diabetes and neurological disorders, and recent progress in the development of therapeutics based on antioxidants, AGE breakers and RAGE inhibitors. Furthermore, this review outlines therapeutic strategies based on single-atom nanozymes that attenuate oxidative stress through the sequestering of reactive oxygen species (ROS) and reactive nitrogen species (RNS).
    Keywords:  4-hydroxy-trans-2-nonenal (HNE); Alzheimer’s disease; diabetes; lipid peroxidation; nanozymes; oxidative stress; reactive nitrogen species; reactive oxygen species; receptors for advanced glycation end products (RAGE)
    DOI:  https://doi.org/10.3390/biomedicines11112925
  6. Int J Mol Sci. 2023 Nov 20. pii: 16536. [Epub ahead of print]24(22):
    The Protective Effects of Reineckia carnea Ether Fraction against Alzheimer's Disease Pathology: An Exploration in Caenorhabditis elegans Models.
    Hai-Jun Fu, Xing-Yue Zhou, Ya-Ping Li, Xue Chen, Yan-Ni He, Da-Lian Qin, Lu Yu, Chong-Lin Yu, Jian-Ming Wu, An-Guo Wu, Xiao-Gang Zhou.
      Alzheimer's disease (AD) presents a significant challenge to global healthcare systems, with current treatments offering only modest relief and often bringing unwanted side effects, necessitating the exploration of more effective and safer drugs. In this study, we employed the Caenorhabditis elegans (C. elegans) model, specifically the AD-like CL4176 strain expressing the human Aβ(1-42) protein, to investigate the potential of Reineckia carnea extract and its fractions. Our results showed that the Reineckia carnea ether fraction (REF) notably diminished the paralysis rates of CL4176 worms. Additionally, REF also attenuated the neurotoxicity effects prompted by Tau proteins in the BR5270 worms. Moreover, REF was observed to counteract the accumulation of Aβ and pTau proteins and their induced oxidative stress in C. elegans AD-like models. Mechanistic studies revealed that REF's benefits were associated with the induction of autophagy in worms; however, these protective effects were nullified when autophagy-related genes were suppressed using RNAi bacteria. Together, these findings highlight Reineckia carnea ether fraction as a promising candidate for AD treatment, warranting further investigation into its autophagy-inducing components and their molecular mechanisms.
    Keywords:  Alzheimer’s disease; Aβ; Reineckia carnea ether fraction; Tau; autophagy
    DOI:  https://doi.org/10.3390/ijms242216536
  7. Biochem Biophys Res Commun. 2023 Nov 14. pii: S0006-291X(23)01334-7. [Epub ahead of print]690 149240
    Early-life caffeine exposure induces morphological changes and altered physiology in Caenorhabditiselegans.
    Lance Kuo-Esser, Ramon Chen, Kylie Lawson, Kennedy Kuchinski, Nijah Simmons, Mauricio Dominguez, Tommy Scandura, Martin Vo, Emma Dasenbrock-Gammon, Natalie Hagan, Haley Esposito, Molly Thompson, Steven Le, Wilber Escorcia, Hanna N Wetzel.
      Caffeine, a widely consumed stimulant, is known for its effects on alertness and fatigue reduction by blockade of adenosine receptors. While it holds therapeutic potential, its diverse impacts pose risks, particularly in early development. This study explores the developmental effects of caffeine exposure using Caenorhabditis elegans (C. elegans) as a model organism. We investigated morphological and behavioral changes induced by caffeine exposure at the L1 stage and assessed their impact at the L4 stage, which roughly corresponds to human infancy and adolescence, respectively. Caffeine-exposed worms displayed increased body length, body bends, and pharyngeal pumping rates compared to control worms. These findings indicate heightened food-seeking behavior and greater food intake, leading to the observed morphological changes. While caffeine did not affect other locomotor behaviors, its stimulatory effect on growth and development highlights its significance. This study provides insights into the potential impact of early-life caffeine exposure on long-term health and development, offering a foundation for future research in vertebrates to uncover its implications on metabolism and other metrics of health.
    Keywords:  Caenorhabditis elegans; Caffeine; Development; Morphology; Physiology
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149240
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