bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023–01–29
eightteen papers selected by
Mikaila Chetty, Goa University
  1. The paradigm of amyloid precursor protein in amyotrophic lateral sclerosis: The potential role of the 682YENPTY687 motif.
  2. Oxidative stress, inflammation and hormesis: The role of dietary and lifestyle modifications on aging.
  3. Interactions between amyloid, amyloid precursor protein, and mitochondria.
  4. The Role of Gut Dysbiosis and Potential Approaches to Target the Gut Microbiota in Multiple Sclerosis.
  5. Amyloid-β in Alzheimer's disease - front and centre after all?
  6. Potential Protective Function of Aβ42 Monomer on Tauopathies.
  7. Challenges and Opportunities of Metal Chelation Therapy in Trace Metals Overload-Induced Alzheimer's Disease.
  8. The expression pattern of GDF15 in human brain changes during aging and in Alzheimer's disease.
  9. The role of altered protein acetylation in neurodegenerative disease.
  10. Gut-derived β-amyloid: Likely a centerpiece of the gut-brain axis contributing to Alzheimer's pathogenesis.
  11. Phage-encoded carbohydrate-interacting proteins in the human gut.
  12. Lipids Uniquely Alter the Secondary Structure and Toxicity of Amyloid beta 1-42 Aggregates.
  13. Multivariate effects of pH, salt, and Zn2+ ions on Aβ40 fibrillation.
  14. Liquid-liquid phase separation of protein tau: An emerging process in Alzheimer's disease pathogenesis.
  15. Microbiota of the gastrointestinal tract: Friend or foe?
  16. The neuroimmune axis of Alzheimer's disease.
  17. Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis.
  18. Ex vivo analysis platforms for monitoring amyloid precursor protein cleavage.
  1. Comput Struct Biotechnol J. 2023 ;21 923-930
    The paradigm of amyloid precursor protein in amyotrophic lateral sclerosis: The potential role of the 682YENPTY687 motif.
    Matrone Carmela.
      Neurodegenerative diseases are characterized by the progressive decline of neuronal function in several brain areas, and are always associated with cognitive, psychiatric, or motor deficits due to the atrophy of certain neuronal populations. Most neurodegenerative diseases share common pathological mechanisms, such as neurotoxic protein misfolding, oxidative stress, and impairment of autophagy machinery. Amyotrophic lateral sclerosis (ALS) is one of the most common adult-onset motor neuron disorders worldwide. It is clinically characterized by the selective and progressive loss of motor neurons in the motor cortex, brain stem, and spinal cord, ultimately leading to muscle atrophy and rapidly progressive paralysis. Multiple recent studies have indicated that the amyloid precursor protein (APP) and its proteolytic fragments are not only drivers of Alzheimer's disease (AD) but also one of the earliest signatures in ALS, preceding or anticipating neuromuscular junction instability and denervation. Indeed, altered levels of APP peptides have been found in the brain, muscles, skin, and cerebrospinal fluid of ALS patients. In this short review, we discuss the nature and extent of research evidence on the role of APP peptides in ALS, focusing on the intracellular C-terminal peptide and its regulatory motif 682YENPTY687, with the overall aim of providing new frameworks and perspectives for intervention and identifying key questions for future investigations.
    Keywords:  682YENPTY687 motif; Amyloid precursor protein; Amyotrophic lateral sclerosis; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.csbj.2023.01.008
  2. Neurochem Int. 2023 Jan 23. pii: S0197-0186(23)00018-9. [Epub ahead of print] 105490
    Oxidative stress, inflammation and hormesis: The role of dietary and lifestyle modifications on aging.
    Vinita Sharma, Mohammad Murtaza Mehdi.
      Oxidative stress (OS) is primarily caused by the formation of free radicals and reactive oxygen species; it is considered as one of the prominent factors in slowing down and degrading cellular machinery of an individual, and it eventually leads to aging and age-related diseases by its continuous higher state. The relation between molecular damage and OS should be particularized to understand the beginning of destruction at the cellular levels, extending outwards to affect tissues, organs, and ultimately to the organism. Several OS biomarkers, which are established at the biomolecular level, are useful in investigating the disease susceptibility during aging. Slowing down the aging process is a matter of reducing the rate of oxidative damage to the cellular machinery over time. The breakdown of homeostasis, the mild overcompensation, the reestablishment of homeostasis, and the adaptive nature of the process are the essential features of hormesis, which incorporates several factors, including calorie restriction, nutrition and lifestyle modifications that play an important role in reducing the OS. In the current review, along with the concept and theories of aging (with emphasis on free radical theory), various manifestations of OS with special attention on mitochondrial dysfunction and age-related diseases have been discussed. To alleviate the OS, hormetic approaches including caloric restriction, exercise, and nutrition have also been discussed.
    Keywords:  Age-related diseases and inflammaging; Aging; Calorie restriction; Hormesis; Oxidative stress and free radicals; Physical activity and nutrition
    DOI:  https://doi.org/10.1016/j.neuint.2023.105490
  3. Biochem Soc Trans. 2023 Jan 23. pii: BST20220518. [Epub ahead of print]
    Interactions between amyloid, amyloid precursor protein, and mitochondria.
    Heather M Wilkins.
      Mitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimer's disease (AD). Decades of research describe a relationship between mitochondrial function and Aβ production. Amyloid precursor protein (APP), of which Aβ is generated from, is found within mitochondria. Studies suggest Aβ can be generated in mitochondria and imported into mitochondria. APP and Aβ alter mitochondrial function, while mitochondrial function alters Aβ production from APP. The role these interactions contribute to AD pathology and progression are unknown. Here, we discuss prior research, the rigor of those studies, and the critical knowledge gaps of relationships between APP, Aβ, and mitochondria.
    Keywords:  Alzheimer's disease; amyloid beta; amyloid precursor protein; bioenergetics; mitochondria; γ-secretase
    DOI:  https://doi.org/10.1042/BST20220518
  4. CNS Drugs. 2023 Jan 24.
    The Role of Gut Dysbiosis and Potential Approaches to Target the Gut Microbiota in Multiple Sclerosis.
    Dimitrios C Ladakis, Pavan Bhargava.
      It has now been established that a perturbation in gut microbiome composition exists in multiple sclerosis (MS) and its interplay with the immune system and brain could potentially contribute to the development of the disease and influence its course. The effects of the gut microbiota on the disease may be mediated by direct interactions between bacteria and immune cells or through interactions of products of bacterial metabolism with immune and CNS cells. In this review article we summarize the ways in which the gut microbiome of people with MS differs from controls and how bacterial metabolites can potentially play a role in MS pathogenesis, and examine approaches to alter the composition of the gut microbiota potentially alleviating gut dysbiosis and impacting the course of MS.
    DOI:  https://doi.org/10.1007/s40263-023-00986-w
  5. Neuronal Signal. 2023 Mar;7(1): NS20220086
    Amyloid-β in Alzheimer's disease - front and centre after all?
    Caroline Weglinski, Alexander Jeans.
      The amyloid hypothesis, which proposes that accumulation of the peptide amyloid-β at synapses is the key driver of Alzheimer's disease (AD) pathogenesis, has been the dominant idea in the field of Alzheimer's research for nearly 30 years. Recently, however, serious doubts about its validity have emerged, largely motivated by disappointing results from anti-amyloid therapeutics in clinical trials. As a result, much of the AD research effort has shifted to understanding the roles of a variety of other entities implicated in pathogenesis, such as microglia, astrocytes, apolipoprotein E and several others. All undoubtedly play an important role, but the nature of this has in many cases remained unclear, partly due to their pleiotropic functions. Here, we propose that all of these AD-related entities share at least one overlapping function, which is the local regulation of amyloid-β levels, and that this may be critical to their role in AD pathogenesis. We also review what is currently known of the actions of amyloid-β at the synapse in health and disease, and consider in particular how it might interact with the key AD-associated protein tau in the disease setting. There is much compelling evidence in support of the amyloid hypothesis; rather than detract from this, the implication of many disparate AD-associated cell types, molecules and processes in the regulation of amyloid-β levels may lend further support.
    Keywords:  Alzheimers disease; Amyloid beta; synapses
    DOI:  https://doi.org/10.1042/NS20220086
  6. J Am Soc Mass Spectrom. 2023 Jan 24.
    Potential Protective Function of Aβ42 Monomer on Tauopathies.
    Amber L H Gray, Victoria Norman, Damilola S Oluwatoba, Rebecca A Prosser, Thanh D Do.
      While soluble forms of amyloid-β (Aβ) and Tau work together to drive healthy neurons into a disease state, how their interaction may control the prion-like propagation and neurotoxicity of Tau is not fully understood. The cross-linking via disulfide bond formation is crucial for Tau oligomers to obtain stable conformers and spread between cells. This work thus focuses on how Aβ42 regulates this critical process. By studying the interactions between Aβ42 and TauPHF43, a construct that mimics the Tau R3 isoform, has a similar length to Aβ42, and contains one cysteine (Cys-322), we discovered that fresh Aβ42 could protect Tau against the formation of disulfide cross-linked dimers. We showed that the monomeric and small Aβ oligomers (the "nonamyloidogenic Aβ") efficiently disassembled tau dimers and heparin-induced Tau oligomers to recover Tau monomers. Interestingly, Aβ serves the role of an antioxidant to prevent disulfide bond formation, as supported by the experiments of Aβ with cystine. Furthermore, using cyclosporine A (CycA), a macrocyclic β-sheet disruptor, we demonstrated that targeting amyloidogenic Aβ with CycA does not affect the TauPHF43 disassembly driven by Aβ42. Separately, we assessed the initial toxicity of Aβ42 and TauPHF43 in acute brain slices and found that Aβ42 is more toxic than TauPHF43 or the two peptides combined. Our work highlights a potential protective role of Aβ42 monomers in AD that was previously overlooked while focusing on the mechanism behind Aβ42 aggregation leading to tau dysfunction.
    Keywords:  Alzheimer’s disease; amyloid-β; amyloids; disulfide bond; mass spectrometry; tau
    DOI:  https://doi.org/10.1021/jasms.2c00343
  7. Neurotox Res. 2023 Jan 27.
    Challenges and Opportunities of Metal Chelation Therapy in Trace Metals Overload-Induced Alzheimer's Disease.
    Vinay Chaudhari, Siddhi Bagwe-Parab, Harpal S Buttar, Shubhangi Gupta, Amisha Vora, Ginpreet Kaur.
      Essential trace metals like zinc (Zn), iron (Fe), and copper (Cu) play an important physiological role in the metabolomics and healthy functioning of body organs, including the brain. However, abnormal accumulation of trace metals in the brain and dyshomeostasis in the different regions of the brain have emerged as contributing factors in neuronal degeneration, Aβ aggregation, and Tau formation. The link between these essential trace metal ions and the risk of AD has been widely studied, although the conclusions have been ambiguous. Despite the absence of evidence for any clinical benefit, therapeutic chelation is still hypothesized to be a therapeutic option for AD. Furthermore, the parameters like bioavailability, ability to cross the BBB, and chelation specificity must be taken into consideration while selecting a suitable chelation therapy. The data in this review summarizes that the primary intervention in AD is brain metal homeostasis along with brain metal scavenging. This review evaluates the impact of different trace metals (Cu, Zn, Fe) on normal brain functioning and their association with neurodegeneration in AD. Also, it investigates the therapeutic potential of metal chelators in the management of AD. An extensive literature search was carried out on the "Web of Science, PubMed, Science Direct, and Google Scholar" to investigate the effect of trace elements in neurological impairment and the role of metal chelators in AD. In addition, the current review highlights the advantages and limitations of chelation therapies and the difficulties involved in developing selective metal chelation therapy in AD patients.
    Keywords:  Alzheimer’s disease; Amyloid-β aggregates; Dyshomeostasis of Cu, Fe, Zn in AD; Metal chelators therapy in AD; Tau formation
    DOI:  https://doi.org/10.1007/s12640-023-00634-7
  8. Front Aging Neurosci. 2022 ;14 1058665
    The expression pattern of GDF15 in human brain changes during aging and in Alzheimer's disease.
    Antonio Chiariello, Sabrina Valente, Gianandrea Pasquinelli, Alessandra Baracca, Gianluca Sgarbi, Giancarlo Solaini, Valentina Medici, Valentina Fantini, Tino Emanuele Poloni, Monica Tognocchi, Marina Arcaro, Daniela Galimberti, Claudio Franceschi, Miriam Capri, Stefano Salvioli, Maria Conte.
       Introduction: Growth Differentiation Factor 15 (GDF15) is a mitochondrial-stress-responsive molecule whose expression strongly increases with aging and age-related diseases. However, its role in neurodegenerative diseases, including Alzheimer's disease (AD), is still debated.
    Methods: We have characterized the expression of GDF15 in brain samples from AD patients and non-demented subjects (controls) of different ages.
    Results: Although no difference in CSF levels of GDF15 was found between AD patients and controls, GDF15 was expressed in different brain areas and seems to be predominantly localized in neurons. The ratio between its mature and precursor form was higher in the frontal cortex of AD patients compared to age-matched controls (p < 0.05). Moreover, this ratio was even higher for centenarians (p < 0.01), indicating that aging also affects GDF15 expression and maturation. A lower expression of OXPHOS complexes I, III, and V in AD patients compared to controls was also noticed, and a positive correlation between GDF15 and IL-6 mRNA levels was observed. Finally, when GDF15 was silenced in vitro in dermal fibroblasts, a decrease in OXPHOS complexes transcript levels and an increase in IL-6 levels were observed.
    Discussion: Although GDF15 seems not to be a reliable CSF marker for AD, it is highly expressed in aging and AD brains, likely as a part of stress response aimed at counteracting mitochondrial dysfunction and neuroinflammation.
    Keywords:  Alzheimer’s disease; GDF15; aging; inflammation; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fnagi.2022.1058665
  9. Front Aging Neurosci. 2022 ;14 1025473
    The role of altered protein acetylation in neurodegenerative disease.
    Fariha Kabir, Rachel Atkinson, Anthony L Cook, Andrew James Phipps, Anna Elizabeth King.
      Acetylation is a key post-translational modification (PTM) involved in the regulation of both histone and non-histone proteins. It controls cellular processes such as DNA transcription, RNA modifications, proteostasis, aging, autophagy, regulation of cytoskeletal structures, and metabolism. Acetylation is essential to maintain neuronal plasticity and therefore essential for memory and learning. Homeostasis of acetylation is maintained through the activities of histone acetyltransferases (HAT) and histone deacetylase (HDAC) enzymes, with alterations to these tightly regulated processes reported in several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Both hyperacetylation and hypoacetylation can impair neuronal physiological homeostasis and increase the accumulation of pathophysiological proteins such as tau, α-synuclein, and Huntingtin protein implicated in AD, PD, and HD, respectively. Additionally, dysregulation of acetylation is linked to impaired axonal transport, a key pathological mechanism in ALS. This review article will discuss the physiological roles of protein acetylation and examine the current literature that describes altered protein acetylation in neurodegenerative disorders.
    Keywords:  HATs; HDACs; PTMs; acetylation; cytoskeleton; neurodegenerative disease; proteostasis
    DOI:  https://doi.org/10.3389/fnagi.2022.1025473
  10. Gut Microbes. 2023 Jan-Dec;15(1):15(1): 2167172
    Gut-derived β-amyloid: Likely a centerpiece of the gut-brain axis contributing to Alzheimer's pathogenesis.
    Jinghua Jin, Zhi Xu, Lina Zhang, Can Zhang, Xiaoduo Zhao, Yuxuan Mao, Haojian Zhang, Xingguang Liang, Juanli Wu, Ying Yang, Jing Zhang.
      Peripheral β-amyloid (Aβ), including those contained in the gut, may contribute to the formation of Aβ plaques in the brain, and gut microbiota appears to exert an impact on Alzheimer's disease (AD) via the gut-brain axis, although detailed mechanisms are not clearly defined. The current study focused on uncovering the potential interactions among gut-derived Aβ in aging, gut microbiota, and AD pathogenesis. To achieve this goal, the expression levels of Aβ and several key proteins involved in Aβ metabolism were initially assessed in mouse gut, with key results confirmed in human tissue. The results demonstrated that a high level of Aβ was detected throughout the gut in both mice and human, and gut Aβ42 increased with age in wild type and mutant amyloid precursor protein/presenilin 1 (APP/PS1) mice. Next, the gut microbiome of mice was characterized by 16S rRNA sequencing, and we found the gut microbiome altered significantly in aged APP/PS1 mice and fecal microbiota transplantation (FMT) of aged APP/PS1 mice increased gut BACE1 and Aβ42 levels. Intra-intestinal injection of isotope or fluorescence labeled Aβ combined with vagotomy was also performed to investigate the transmission of Aβ from gut to brain. The data showed that, in aged mice, the gut Aβ42 was transported to the brain mainly via blood rather than the vagal nerve. Furthermore, FMT of APP/PS1 mice induced neuroinflammation, a phenotype that mimics early AD pathology. Taken together, this study suggests that the gut is likely a critical source of Aβ in the brain, and gut microbiota can further upregulate gut Aβ production, thereby potentially contributing to AD pathogenesis.
    Keywords:  Alzheimer’s disease; aging; cognition; gut microbiota; gut–brain axis; β-amyloid
    DOI:  https://doi.org/10.1080/19490976.2023.2167172
  11. Front Microbiol. 2022 ;13 1083208
    Phage-encoded carbohydrate-interacting proteins in the human gut.
    Daniela Rothschild-Rodriguez, Morgen Hedges, Merve Kaplan, Sercan Karav, Franklin L Nobrega.
      In the human gastrointestinal tract, the gut mucosa and the bacterial component of the microbiota interact and modulate each other to accomplish a variety of critical functions. These include digestion aid, maintenance of the mucosal barrier, immune regulation, and production of vitamins, hormones, and other metabolites that are important for our health. The mucus lining of the gut is primarily composed of mucins, large glycosylated proteins with glycosylation patterns that vary depending on factors including location in the digestive tract and the local microbial population. Many gut bacteria have evolved to reside within the mucus layer and thus encode mucus-adhering and -degrading proteins. By doing so, they can influence the integrity of the mucus barrier and therefore promote either health maintenance or the onset and progression of some diseases. The viral members of the gut - mostly composed of bacteriophages - have also been shown to have mucus-interacting capabilities, but their mechanisms and effects remain largely unexplored. In this review, we discuss the role of bacteriophages in influencing mucosal integrity, indirectly via interactions with other members of the gut microbiota, or directly with the gut mucus via phage-encoded carbohydrate-interacting proteins. We additionally discuss how these phage-mucus interactions may influence health and disease states.
    Keywords:  bacteriophage; glycans; glycosylation; gut; mucins; mucus; mucus-binding; mucus-degrading
    DOI:  https://doi.org/10.3389/fmicb.2022.1083208
  12. FEBS J. 2023 Jan 27.
    Lipids Uniquely Alter the Secondary Structure and Toxicity of Amyloid beta 1-42 Aggregates.
    Kiryl Zhaliazka, Mikhail Matveyenka, Dmitry Kurouski.
      Abrupt aggregation of amyloid β1-42 (Aβ) peptide is a hallmark of Alzheimer's disease (AD), a severe pathology that affects more than 44 million people worldwide. A growing body of evidence suggests that lipids can uniquely alter rates of Aβ1-42 aggregation. However, it remains unclear whether lipids only alter rates of protein aggregation or also uniquely modify the secondary structure and toxicity of Aβ1-42 oligomers and fibrils. In this study, we investigated the effect of phosphatidylcholine (PC), cardiolipin (CL), and cholesterol (Chol) on Aβ1-42 aggregation. We found that PC, CL and Chol strongly accelerated the rate of fibril formation compared to the rate of Aβ1-42 aggregation in the lipid-free environment. Furthermore, anionic CL enabled the strongest acceleration of Aβ1-42 aggregation compared to zwitterionic PC and uncharged Chol. We also found that PC, CL, and Chol uniquely altered the secondary structure of early-, middle- and late-stage Aβ1-42 aggregates. Specifically, CL and Chol drastically increased the amount of parallel β-sheet in Aβ1-42 oligomers and fibrils grown in the presence of these lipids. This caused a significant increase in the toxicity of Aβ:CL and Aβ:Chol compared to the toxicity of Aβ:PC and Aβ1-42 aggregates formed in the lipid-free environment. These results demonstrate that toxicity of Aβ aggregates correlates with the amount of their β-sheet content, which, in turn, is determined by the chemical structure of lipids present at the stage of Aβ1-42 aggregation.
    Keywords:  AFM-IR; amyloid β1-42; phospholipids; fibrils; oligomers
    DOI:  https://doi.org/10.1111/febs.16738
  13. Commun Chem. 2022 Dec 13. 5(1): 171
    Multivariate effects of pH, salt, and Zn2+ ions on Aβ40 fibrillation.
    Hongzhi Wang, Jinming Wu, Rebecca Sternke-Hoffmann, Wenwei Zheng, Cecilia Mörman, Jinghui Luo.
      Amyloid-β (Aβ) peptide aggregation plays a central role in the progress of Alzheimer's disease (AD), of which Aβ-deposited extracellular amyloid plaques are a major hallmark. The brain micro-environmental variation in AD patients, like local acidification, increased ionic strength, or changed metal ion levels, cooperatively modulates the aggregation of the Aβ peptides. Here, we investigate the multivariate effects of varied pH, ionic strength and Zn2+ on Aβ40 fibrillation kinetics. Our results reveal that Aβ fibrillation kinetics are strongly affected by pH and ionic strength suggesting the importance of electrostatic interactions in regulating Aβ40 fibrillation. More interestingly, the presence of Zn2+ ions can further alter or even reserve the role of pH and ionic strength on the amyloid fibril kinetics, suggesting the importance of amino acids like Histidine that can interact with Zn2+ ions. Both pH and ionic strength regulate the secondary nucleation processes, however regardless of pH and Zn2+ ions, ionic strength can also modulate the morphology of Aβ40 aggregates. These multivariate effects in bulk solution provide insights into the correlation of pH-, ionic strength- or Zn2+ ions changes with amyloid deposits in AD brain and will deepen our understanding of the molecular pathology in the local brain microenvironment.
    DOI:  https://doi.org/10.1038/s42004-022-00786-1
  14. Neurobiol Dis. 2023 Jan 23. pii: S0969-9961(23)00025-6. [Epub ahead of print]178 106011
    Liquid-liquid phase separation of protein tau: An emerging process in Alzheimer's disease pathogenesis.
    Hassan Ainani, Najat Bouchmaa, Reda Ben Mrid, Rachid El Fatimy.
      Metabolic reactions within cells occur in various isolated compartments with or without borders, the latter being known as membrane-less organelles (MLOs). The MLOs show liquid-like properties and are formed by a process known as liquid-liquid phase separation (LLPS). MLOs contribute to different molecules interactions such as protein-protein, protein-RNA, and RNA-RNA driven by various factors, such as multivalency of intrinsic disorders. MLOs are involved in several cell signaling pathways such as transcription, immune response, and cellular organization. However, disruption of these processes has been found in different pathologies. Recently, it has been demonstrated that protein aggregates, a characteristic of some neurodegenerative diseases, undergo similar phase separation. Tau protein is known as a major neurofibrillary tangles component in Alzheimer's disease (AD). This protein can undergo phase separation to form a MLO known as tau droplet in vitro and in vivo, and this process can be facilitated by several factors, including crowding agents, RNA, and phosphorylation. Tau droplet has been shown to mature into insoluble aggregates suggesting that this process may precede and induce neurodegeneration in AD. Here we review major factors involved in liquid droplet formation within a cell. Additionally, we highlight recent findings concerning tau aggregation following phase separation in AD, along with the potential therapeutic strategies that could be explored in this process against the progression of this pathology.
    Keywords:  Alzheimer's disease; Liquid droplet; Membrane-less organelle; Phase separation; Tau aggregation
    DOI:  https://doi.org/10.1016/j.nbd.2023.106011
  15. World J Gastroenterol. 2023 Jan 07. 29(1): 19-42
    Microbiota of the gastrointestinal tract: Friend or foe?
    Marina A Senchukova.
      The gut microbiota is currently considered an external organ of the human body that provides important mechanisms of metabolic regulation and protection. The gut microbiota encodes over 3 million genes, which is approximately 150 times more than the total number of genes present in the human genome. Changes in the qualitative and quantitative composition of the microbiome lead to disruption in the synthesis of key bacterial metabolites, changes in intestinal barrier function, and inflammation and can cause the development of a wide variety of diseases, such as diabetes, obesity, gastrointestinal disorders, cardiovascular issues, neurological disorders and oncological concerns. In this review, I consider issues related to the role of the microbiome in the regulation of intestinal barrier function, its influence on physiological and pathological processes occurring in the body, and potential new therapeutic strategies aimed at restoring the gut microbiome. Herewith, it is important to understand that the gut microbiota and human body should be considered as a single biological system, where change of one element will inevitably affect its other components. Thus, the study of the impact of the intestinal microbiota on health should be considered only taking into account numerous factors, the role of which has not yet been fully elucidated.
    Keywords:  Bacterial metabolites; Dysbiosis; Fecal microbiota transplantation; Gut microbiota; Intestinal barrier; Probiotics
    DOI:  https://doi.org/10.3748/wjg.v29.i1.19
  16. Genome Med. 2023 Jan 26. 15(1): 6
    The neuroimmune axis of Alzheimer's disease.
    Mehdi Jorfi, Anna Maaser-Hecker, Rudolph E Tanzi.
      Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder with multifaceted neuropathological features, including β-amyloid plaques, neurofibrillary tangles, and neuroinflammation. Over the past decade, emerging evidence has implicated both beneficial and pathological roles for innate immune genes and immune cells, including peripheral immune cells such as T cells, which can infiltrate the brain and either ameliorate or exacerbate AD neuropathogenesis. These findings support a neuroimmune axis of AD, in which the interplay of adaptive and innate immune systems inside and outside the brain critically impacts the etiology and pathogenesis of AD. In this review, we discuss the complexities of AD neuropathology at the levels of genetics and cellular physiology, highlighting immune signaling pathways and genes associated with AD risk and interactions among both innate and adaptive immune cells in the AD brain. We emphasize the role of peripheral immune cells in AD and the mechanisms by which immune cells, such as T cells and monocytes, influence AD neuropathology, including microglial clearance of amyloid-β peptide, the key component of β-amyloid plaque cores, pro-inflammatory and cytotoxic activity of microglia, astrogliosis, and their interactions with the brain vasculature. Finally, we review the challenges and outlook for establishing immune-based therapies for treating and preventing AD.
    Keywords:  Alzheimer’s disease; Heterogeneity; Immune system; Neuroimmune; β-amyloid
    DOI:  https://doi.org/10.1186/s13073-023-01155-w
  17. World J Gastroenterol. 2023 Jan 07. 29(1): 144-156
    Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis.
    Ming Luo, Rui-Juan Xin, Fang-Rui Hu, Li Yao, Sheng-Juan Hu, Fei-Hu Bai.
      Minimal hepatic encephalopathy (MHE) is a frequent neurological and psychiatric complication of liver cirrhosis. The precise pathogenesis of MHE is complicated and has yet to be fully elucidated. Studies in cirrhotic patients and experimental animals with MHE have indicated that gut microbiota dysbiosis induces systemic inflammation, hyperammonemia, and endotoxemia, subsequently leading to neuroinflammation in the brain via the gut-liver-brain axis. Related mechanisms initiated by gut microbiota dysbiosis have significant roles in MHE pathogenesis. The currently available therapeutic strategies for MHE in clinical practice, including lactulose, rifaximin, probiotics, synbiotics, and fecal microbiota transplantation, exert their effects mainly by modulating gut microbiota dysbiosis. Microbiome therapies for MHE have shown promised efficacy and safety; however, several controversies and challenges regarding their clinical use deserve to be intensively discussed. We have summarized the latest research findings concerning the roles of gut microbiota dysbiosis in the pathogenesis of MHE via the gut-liver-brain axis as well as the potential mechanisms by which microbiome therapies regulate gut microbiota dysbiosis in MHE patients.
    Keywords:  Gut microbiota; Gut-liver-brain axis; Minimal hepatic encephalopathy; Pathogenesis; Therapeutics
    DOI:  https://doi.org/10.3748/wjg.v29.i1.144
  18. Front Mol Neurosci. 2022 ;15 1068990
    Ex vivo analysis platforms for monitoring amyloid precursor protein cleavage.
    Yuji Kamikubo, Hao Jin, Yiyao Zhou, Kazue Niisato, Yoshie Hashimoto, Nobumasa Takasugi, Takashi Sakurai.
      Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most common cause of dementia in the elderly. The presence of large numbers of senile plaques, neurofibrillary tangles, and cerebral atrophy is the characteristic feature of AD. Amyloid β peptide (Aβ), derived from the amyloid precursor protein (APP), is the main component of senile plaques. AD has been extensively studied using methods involving cell lines, primary cultures of neural cells, and animal models; however, discrepancies have been observed between these methods. Dissociated cultures lose the brain's tissue architecture, including neural circuits, glial cells, and extracellular matrix. Experiments with animal models are lengthy and require laborious monitoring of multiple parameters. Therefore, it is necessary to combine these experimental models to understand the pathology of AD. An experimental platform amenable to continuous observation and experimental manipulation is required to analyze long-term neuronal development, plasticity, and progressive neurodegenerative diseases. In the current study, we provide a practical method to slice and cultivate rodent hippocampus to investigate the cleavage of APP and secretion of Aβ in an ex vivo model. Furthermore, we provide basic information on Aβ secretion using slice cultures. Using our optimized method, dozens to hundreds of long-term stable slice cultures can be coordinated simultaneously. Our findings are valuable for analyses of AD mouse models and senile plaque formation culture models.
    Keywords:  Alzheimer’s disease; amyloid β; hippocampus; neurodegenerative disease; organotypic brain culture; secretase
    DOI:  https://doi.org/10.3389/fnmol.2022.1068990
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