bims-metalz 2023-04-23 papers

bims-metalz

Biomed News

on Metabolic causes of Alzheimer’s disease

Issue of 2023–04–23
ten papers selected by
Mikaila Chetty, Goa University

Gut microbiota and its metabolites: Bridge of dietary nutrients and Alzheimer's disease.
Microbiota-gut-brain axis and related therapeutics in Alzheimer's disease: prospects for multitherapy and inflammation control.
Dietary neoagarotetraose extends lifespan and impedes brain aging in mice via regulation of microbiota-gut-brain axis.
Gut microbiome-modulated dietary strategies in EAE and multiple sclerosis.
Mitochondrial dynamics in neurological diseases: a narrative review.
A review of the "metallome" within neurons and glia, as revealed by elemental mapping of brain tissue.
Role of Interaction between Zinc and Amyloid Beta in Pathogenesis of Alzheimer's Disease.
T cell aging and Alzheimer's disease.
Parkinson's Disease Risk and Hyperhomocysteinemia: The Possible Link.
Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration.

Adv Nutr. 2023 Apr 17. pii: S2161-8313(23)00290-9. [Epub ahead of print]

Gut microbiota and its metabolites: Bridge of dietary nutrients and Alzheimer's disease.

Guangsu Zhu, Jianxin Zhao, Hao Zhang, Gang Wang, Wei Chen.

  Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment and neuroinflammation. Recent research has revealed the crucial role of the gut microbiota and microbial metabolites in modulating AD. However, mechanisms by which the microbiome and microbial metabolites affect brain function remain poorly understood. Here, we review the literature on changes in the diversity and composition of the gut microbiome in AD patients and in animal models of AD. We also discuss the latest progress in understanding the pathways by which the gut microbiota and microbial metabolites from the host or diet regulate AD. By understanding the effects of dietary components on brain function, the microbiota composition and microbial metabolites, we examine the potential for manipulation of the gut microbiota through dietary intervention to delay the progress of AD. Although it is challenging to translate our understanding of microbiome-based approaches to dietary guidelines or clinical therapies, these findings provide an attractive target for promoting brain function.

Keywords:  Alzheimer’s disease; Dietary interventions; Gut microbiota; Microbial metabolites; Microbiota-gut-brain axis

DOI:  https://doi.org/10.1016/j.advnut.2023.04.005
Rev Neurosci. 2023 Apr 20.

Microbiota-gut-brain axis and related therapeutics in Alzheimer's disease: prospects for multitherapy and inflammation control.

Jiahao Li, Feng Zhang, Li Zhao, Chunbo Dong.

  Alzheimer's disease (AD) is the most common type of dementia in the elderly and causes neurodegeneration, leading to memory loss, behavioral disorder, and psychiatric impairment. One potential mechanism contributing to the pathogenesis of AD may be the imbalance in gut microbiota, local and systemic inflammation, and dysregulation of the microbiota-gut-brain axis (MGBA). Most of the AD drugs approved for clinical use today are symptomatic treatments that do not improve AD pathologic changes. As a result, researchers are exploring novel therapeutic modalities. Treatments involving the MGBA include antibiotics, probiotics, transplantation of fecal microbiota, botanical products, and others. However, single-treatment modalities are not as effective as expected, and a combination therapy is gaining momentum. The purpose of this review is to summarize recent advances in MGBA-related pathological mechanisms and treatment modalities in AD and to propose a new concept of combination therapy. "MGBA-based multitherapy" is an emerging view of treatment in which classic symptomatic treatments and MGBA-based therapeutic modalities are used in combination. Donepezil and memantine are two commonly used drugs in AD treatment. On the basis of the single/combined use of these two drugs, two/more additional drugs and treatment modalities that target the MGBA are chosen based on the characteristics of the patient's condition as an adjuvant treatment, as well as the maintenance of good lifestyle habits. "MGBA-based multitherapy" offers new insights for the treatment of cognitive impairment in AD patients and is expected to show good therapeutic results.

Keywords:  Alzheimer’s disease; combination therapy; gut microbiota; inflammatory factors; microbiota-gut-brain axis

DOI:  https://doi.org/10.1515/revneuro-2023-0006
J Adv Res. 2023 Apr 19. pii: S2090-1232(23)00120-0. [Epub ahead of print]

Dietary neoagarotetraose extends lifespan and impedes brain aging in mice via regulation of microbiota-gut-brain axis.

Tao Li, Shaoqing Yang, Xiaoyan Liu, Yanxiao Li, Zhenglong Gu, Zhengqiang Jiang.

   INTRODUCTION: Dietary oligosaccharides can impact the gut microbiota and confer tremendous health benefits.
OBJECTIVES: The aim of this study was to determine the impact of a novel functional oligosaccharide, neoagarotetraose (NAT), on aging in mice.
METHODS: 8-month-old C57BL/6J mice as the natural aging mice model were orally administered with NAT for 12 months. The preventive effect of NAT in Alzheimer's disease (AD) mice was further evaluated. Aging related indicators, neuropathology, gut microbiota and short-chain fatty acids (SCFAs) in cecal contents were analyzed.
RESULTS: NAT treatment extended the lifespan of these mice by up to 33.3%. Furthermore, these mice showed the improved aging characteristics and decreased injuries in cerebral neurons. Dietary NAT significantly delayed DNA damage in the brain, and inhibited reduction of tight junction protein in the colon. A significant increase at gut bacterial genus level (such as Lactobacillus, Butyricimonas, and Akkermansia) accompanied by increasing concentrations of SCFAs in cecal contents was observed after NAT treatment. Functional profiling of gut microbiota composition indicated that NAT treatment regulated the glucolipid and bile acid-related metabolic pathways. Interestingly, NAT treatment ameliorated cognitive impairment, attenuated amyloid-β (Aβ) and Tau pathology, and regulated the gut microbiota composition and SCFAs receptor-related pathway of Alzheimer's disease (AD) mice.
CONCLUSION: NAT mitigated age-associated cerebral injury in mice through gut-brain axis. The findings provide novel evidence for the effect of NAT on anti-aging, and highlight the potential application of NAT as an effective intervention against age-related diseases.

Keywords:  Alzheimer’s disease; gut microbiota; longevity; neoagarotetraose; neuronal injury

DOI:  https://doi.org/10.1016/j.jare.2023.04.014
Front Nutr. 2023 ;10 1146748

Gut microbiome-modulated dietary strategies in EAE and multiple sclerosis.

Kristina Hoffman, William J Doyle, Sean M Schumacher, Javier Ochoa-Repáraz.

  Over the last few decades, the incidence of multiple sclerosis has increased as society's dietary habits have switched from a whole foods approach to a high fat, high salt, low dietary fiber, and processed food diet, termed the "Western diet." Environmental factors, such as diet, could play a role in the pathogenesis of multiple sclerosis due to gut microbiota alterations, gut barrier leakage, and subsequent intestinal inflammation that could lead to exacerbated neuroinflammation. This mini-review explores the gut microbiome alterations of various dietary strategies that improve upon the "Western diet" as promising alternatives and targets to current multiple sclerosis treatments. We also provide evidence that gut microbiome modulation through diet can improve or exacerbate clinical symptoms of multiple sclerosis, highlighting the importance of including gut microbiome analyses in future studies of diet and disease.

Keywords:  EAE; diet; dietary factors; dietary interventions; gut dysbiosis; gut microbiome; multiple sclerosis

DOI:  https://doi.org/10.3389/fnut.2023.1146748
Ann Transl Med. 2023 Mar 31. 11(6): 264

Mitochondrial dynamics in neurological diseases: a narrative review.

Yue Shen, Wen-Li Jiang, Xin Li, Ai-Lin Cao, Dan Li, Shang-Ze Li, Jun Yang, Jiao Qian.

   Background and Objective: The mitochondrion is a crucial organelle for aerobic respiration and energy metabolism. It undergoes dynamic changes, including changes in its shape, function, and distribution through fission, fusion, and movement. Under normal conditions, mitochondrial dynamics are in homeostasis. However, once the balance is upset, the nervous system, which has high metabolic demands, will most likely be affected. Recent studies have shown that the imbalance of mitochondrial dynamics is involved in the occurrence and development of various neurological diseases. However, whether the regulation of mitochondrial dynamics can be used to treat neurological diseases is still unclear. We aimed to comprehensively analyze mitochondrial dynamics regulation and its potential role in the treatment of neurological diseases.
Methods: A comprehensive literature review was carried out to understand the mechanisms and applications of mitochondrial dynamics in neurological diseases based on the literature available in PubMed, Web of Science, and Google Scholar.
Key Content and Findings: This review discusses the molecular mechanisms related to mitochondrial dynamics and expounds upon the role of mitochondrial dynamics in the occurrence and development of neurodegenerative diseases, epilepsy, cerebrovascular disease, and brain tumors. Several clinically tested drugs with fewer side effects have been shown to improve the mitochondrial dynamics and nervous system function in neurological diseases.
Conclusions: Disorders of mitochondrial dynamics can cause various neurological diseases. Elucidation of mechanisms and applications involved in mitochondrial dynamics will inform the development of new therapeutic targets and strategies for neurological diseases. Dynamin-related protein 1 (Drp1), as a highly relevant molecular for mitochondrial dynamics, might be a potential target for treating neurological diseases in the future.

Keywords:  Alzeimer’s disease; Drp1; Parkinson’s disease; mitochondrial dynamics; mitochondrial fusion protein

DOI:  https://doi.org/10.21037/atm-22-2401
BBA Adv. 2022 ;2 100038

A review of the "metallome" within neurons and glia, as revealed by elemental mapping of brain tissue.

Gaewyn Ellison, Ashley L Hollings, Mark J Hackett.

  It is now well established that transition metals, such as Iron (Fe), Copper (Cu), and Zinc (Zn) are necessary for healthy brain function. Although Fe, Cu, and Zn are essential to the brain, imbalances in the amount, distribution, or chemical form ("metallome") of these metals is linked to the pathology of numerous brain diseases or disorders. Despite the known importance of metal ions for both brain health and disease, the metallome that exists within specific types of brain cells is yet to be fully characterised. The aim of this mini-review is to present an overview of the current knowledge of the metallome found within specific brain cells (oligodendrocytes, astrocytes, microglia, and neurons), as revealed by direct elemental mapping techniques. It is hoped this review will foster continued research using direct elemental mapping techniques to fully characterise the brain cell metallome.

Keywords:  Hippocampus; Metals; Microscopy; Neurodegeneration; Neuroscience

DOI:  https://doi.org/10.1016/j.bbadva.2021.100038
Biochemistry (Mosc). 2023 Jan;88(Suppl 1): S75-S87

Role of Interaction between Zinc and Amyloid Beta in Pathogenesis of Alzheimer's Disease.

Sergey A Kozin.

  Progression of Alzheimer's disease is accompanied by the appearance of extracellular deposits in the brain tissues of patients with characteristic supramolecular morphology (amyloid plaques) the main components of which are β-amyloid isoforms (Aβ) and biometal ions (zinc, copper, iron). For nearly 40 years and up to the present time, the vast majority of experimental data indicate critical role of formation and accumulation of amyloid plaques (cerebral amyloidogenesis) in pathogenesis of Alzheimer's disease, however, nature of the molecular agents that initiate cerebral amyloidogenesis, as well as causes of aggregation of the native Aβ molecules in vivo remained unknown for a long time. This review discusses the current level of fundamental knowledge about the molecular mechanisms of interactions of zinc ions with a number of Aβ isoforms present in amyloid plaques of the patients with Alzheimer's disease, and also shows how this knowledge made it possible to identify driving forces of the cerebral amyloidogenesis in Alzheimer's disease and made it possible to determine fundamentally new biomarkers and drug targets as part of development of innovative strategy for diagnosis and treatment of Alzheimer's disease.

Keywords:  Alzheimer’s disease; amyloid plaques; amyloid-β; biomarker; drug target; oligomerization; zinc complex

DOI:  https://doi.org/10.1134/S0006297923140055
Front Immunol. 2023 ;14 1154699

T cell aging and Alzheimer's disease.

Lin Guo, Xiaoting Li, Timothy Gould, Zhan-You Wang, Wenqiang Cao.

  The brain has long been considered an immune-privileged organ due to the presence of the blood-brain barrier (BBB). However, recent discoveries have revealed the underestimated role of T cells in the brain through the meningeal lymphatic system. Age is the primary risk factor for Alzheimer's disease (AD), resulting in marked age-dependent changes in T cells. Manipulating peripheral T cell immune response has been shown to impact AD, but the relationship between T cell aging and AD remains poorly understood. Given the limited success of targeting amyloid beta (Aβ) and the growing evidence of T cells' involvement in non-lymphoid organ aging, a deeper understanding of the relationship between T cells and AD in the context of aging is crucial for advancing therapeutic progress. In this review, we comprehensively examine existing studies on T cells and AD and offer an integrated perspective on their interconnections in the context of aging. This understanding can inform the development of new interventions to prevent or treat AD.

Keywords:  Alzheimer’s disease (AD); T cell aging; neuroinflammation; senescence; thymic involution

DOI:  https://doi.org/10.3389/fimmu.2023.1154699
Cell Mol Neurobiol. 2023 Apr 19.

Parkinson's Disease Risk and Hyperhomocysteinemia: The Possible Link.

Hayder M Al-Kuraishy, Ali I Al-Gareeb, Yaser Hosny Ali Elewa, Mahmoud Hosny Zahran, Athanasios Alexiou, Marios Papadakis, Gaber El-Saber Batiha.

  Parkinson's disease (PD) is one of the most common degenerative brain disorders caused by the loss of dopaminergic neurons in the substantia nigra (SN). Lewy bodies and -synuclein accumulation in the SN are hallmarks of the neuropathology of PD. Due to lifestyle changes and prolonged L-dopa administration, patients with PD frequently have vitamin deficiencies, especially folate, vitamin B6, and vitamin B12. These disorders augment circulating levels of Homocysteine with the development of hyperhomocysteinemia, which may contribute to the pathogenesis of PD. Therefore, this review aimed to ascertain if hyperhomocysteinemia may play a part in oxidative and inflammatory signaling pathways that contribute to PD development. Hyperhomocysteinemia is implicated in the pathogenesis of neurodegenerative disorders, including PD. Hyperhomocysteinemia triggers the development and progression of PD by different mechanisms, including oxidative stress, mitochondrial dysfunction, apoptosis, and endothelial dysfunction. Particularly, the progression of PD is linked with high inflammatory changes and systemic inflammatory disorders. Hyperhomocysteinemia induces immune activation and oxidative stress. In turn, activated immune response promotes the development and progression of hyperhomocysteinemia. Therefore, hyperhomocysteinemia-induced immunoinflammatory disorders and abnormal immune response may aggravate abnormal immunoinflammatory in PD, leading to more progression of PD severity. Also, inflammatory signaling pathways like nuclear factor kappa B (NF-κB) and nod-like receptor pyrin 3 (NLRP3) inflammasome and other signaling pathways are intricate in the pathogenesis of PD. In conclusion, hyperhomocysteinemia is involved in the development and progression of PD neuropathology either directly via induction degeneration of dopaminergic neurons or indirectly via activation of inflammatory signaling pathways.

Keywords:  Degenerative brain disorders; Hyperhomocysteinemia; Parkinson's disease

DOI:  https://doi.org/10.1007/s10571-023-01350-8
Autophagy Rep. 2023 ;pii: 2166722. [Epub ahead of print]2(1):

Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration.

Ron Benyair, Sai Srinivas Panapakkam Giridharan, Pilar Rivero-Ríos, Junya Hasegawa, Emily Bristow, Eeva-Liisa Eskelinen, Merav D Shmueli, Vered Fishbain-Yoskovitz, Yifat Merbl, Lisa M Sharkey, Henry L Paulson, Phyllis I Hanson, Samarjit Patnaik, Ismael Al-Ramahi, Juan Botas, Juan Marugan, Lois S Weisman.

  Many neurodegenerative diseases, including Huntington's disease (HD) and Alzheimer's disease (AD), occur due to an accumulation of aggregation-prone proteins, which results in neuronal death. Studies in animal and cell models show that reducing the levels of these proteins mitigates disease phenotypes. We previously reported a small molecule, NCT-504, which reduces cellular levels of mutant huntingtin (mHTT) in patient fibroblasts as well as mouse striatal and cortical neurons from an HdhQ111 mutant mouse. Here, we show that NCT-504 has a broader potential, and in addition reduces levels of Tau, a protein associated with Alzheimer's disease, as well as other tauopathies. We find that in untreated cells, Tau and mHTT are degraded via autophagy. Notably, treatment with NCT-504 diverts these proteins to multivesicular bodies (MVB) and the ESCRT pathway. Specifically, NCT-504 causes a proliferation of endolysosomal organelles including MVB, and an enhanced association of mHTT and Tau with endosomes and MVB. Importantly, depletion of proteins that act late in the ESCRT pathway blocked NCT-504 dependent degradation of Tau. Moreover, NCT-504-mediated degradation of Tau occurred in cells where Atg7 is depleted, which indicates that this pathway is independent of canonical autophagy. Together, these studies reveal that upregulation of traffic through an ESCRT-dependent MVB pathway may provide a therapeutic approach for neurodegenerative diseases.

Keywords:  ESCRT; Huntington; NCT-504; Neurodegeneration; Tau; huntingtin; multivesicular bodies (MVB)

DOI:  https://doi.org/10.1080/27694127.2023.2166722