bims-metalz 2022-11-27 papers

bims-metalz

Biomed News

on Metabolic causes of Alzheimer’s disease

Issue of 2022‒11‒27
twenty papers selected by
Mikaila Chetty
Goa University

A review of the preclinical and clinical studies on the role of the gut microbiome in aging and neurodegenerative diseases and its modulation.
Redox signaling and metabolism in Alzheimer's disease.
Activating mitofusins interrupts mitochondrial degeneration and delays disease progression in SOD1 mutant amyotrophic lateral sclerosis.
Animal Models of Cognitive Deficits for Probiotic Treatment.
What Are the Key Gut Microbiota Involved in Neurological Diseases? A Systematic Review.
Role of the gut microbiome in multiple sclerosis: From etiology to therapeutics.
Low-Carbohydrate High-Fat Diet: A SWOC Analysis.
The Role of Insulin Signaling in Hippocampal-Related Diseases: A Focus on Alzheimer's Disease.
Neurodegenerative Diseases: From Dysproteostasis, Altered Calcium Signalosome to Selective Neuronal Vulnerability to AAV-Mediated Gene Therapy.
Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer's Disease and Identifying Promising Drug Targets.
Amyloidogenesis: What Do We Know So Far?
Copper homeostasis and cuproptosis in health and disease.
Interdisciplinary Approaches to Deal with Alzheimer's Disease-From Bench to Bedside: What Feasible Options Do Already Exist Today?
Introduction: Unraveling the complex contributions of indigenous microbes to neurological health and disease.
Therapeutic Potential of Targeting Mitochondria for Alzheimer's Disease Treatment.
The Alterations and Roles of Glycosaminoglycans in Human Diseases.
Iron Supplementation in Pregnancy and Risk of Gestational Diabetes: A Narrative Review.
Multi-Omics Nutritional Approaches Targeting Metabolic-Associated Fatty Liver Disease.
Prohibitins in neurodegeneration and mitochondrial homeostasis.
Retinal Microvascular Dysfunction Occurs Early and Similarly in Mild Alzheimer's Disease and Primary-Open Angle Glaucoma Patients.

Front Cell Neurosci. 2022 ;16 1007166

A review of the preclinical and clinical studies on the role of the gut microbiome in aging and neurodegenerative diseases and its modulation.

Haslin Madihah Hashim, Suzana Makpol.

  As the world population ages, the burden of age-related health problems grows, creating a greater demand for new novel interventions for healthy aging. Advancing aging is related to a loss of beneficial mutualistic microbes in the gut microbiota caused by extrinsic and intrinsic factors such as diet, sedentary lifestyle, sleep deprivation, circadian rhythms, and oxidative stress, which emerge as essential elements in controlling and prolonging life expectancy of healthy aging. This condition is known as gut dysbiosis, and it affects normal brain function via the brain-gut microbiota (BGM) axis, which is a bidirectional link between the gastrointestinal tract (GIT) and the central nervous system (CNS) that leads to the emergence of brain disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Here, we reviewed the role of the gut microbiome in aging and neurodegenerative diseases, as well as provided a comprehensive review of recent findings from preclinical and clinical studies to present an up-to-date overview of recent advances in developing strategies to modulate the intestinal microbiome by probiotic administration, dietary intervention, fecal microbiota transplantation (FMT), and physical activity to address the aging process and prevent neurodegenerative diseases. The findings of this review will provide researchers in the fields of aging and the gut microbiome design innovative studies that leverage results from preclinical and clinical studies to better understand the nuances of aging, gut microbiome, and neurodegenerative diseases.

Keywords:  aging; brain-gut-microbiota axis; gut microbiome; interventions; neurodegenerative diseases

DOI:  https://doi.org/10.3389/fncel.2022.1007166
Front Aging Neurosci. 2022 ;14 1003721

Redox signaling and metabolism in Alzheimer's disease.

M I Holubiec, M Gellert, E M Hanschmann.

  Reduction and oxidation reactions are essential for biochemical processes. They are part of metabolic pathways and signal transduction. Reactive oxygen species (ROS) as second messengers and oxidative modifications of cysteinyl (Cys) residues are key to transduce and translate intracellular and intercellular signals. Dysregulation of cellular redox signaling is known as oxidative distress, which has been linked to various pathologies, including neurodegeneration. Alzheimer's disease (AD) is a neurodegenerative pathology linked to both, abnormal amyloid precursor protein (APP) processing, generating Aβ peptide, and Tau hyperphosphorylation and aggregation. Signs of oxidative distress in AD include: increase of ROS (H2O2, O2 •-), decrease of the levels or activities of antioxidant enzymes, abnormal oxidation of macromolecules related to elevated Aβ production, and changes in mitochondrial homeostasis linked to Tau phosphorylation. Interestingly, Cys residues present in APP form disulfide bonds that are important for intermolecular interactions and might be involved in the aggregation of Aβ. Moreover, two Cys residues in some Tau isoforms have been shown to be essential for Tau stabilization and its interaction with microtubules. Future research will show the complexities of Tau, its interactome, and the role that Cys residues play in the progression of AD. The specific modification of cysteinyl residues in redox signaling is also tightly connected to the regulation of various metabolic pathways. Many of these pathways have been found to be altered in AD, even at very early stages. In order to analyze the complex changes and underlying mechanisms, several AD models have been developed, including animal models, 2D and 3D cell culture, and ex-vivo studies of patient samples. The use of these models along with innovative, new redox analysis techniques are key to further understand the importance of the redox component in Alzheimer's disease and the identification of new therapeutic targets in the future.

Keywords:  APP; Alzheimer's disease; Tau; neurodegeneration; redox metabolism; redox signaling

DOI:  https://doi.org/10.3389/fnagi.2022.1003721
Hum Mol Genet. 2022 Nov 23. pii: ddac287. [Epub ahead of print]

Activating mitofusins interrupts mitochondrial degeneration and delays disease progression in SOD1 mutant amyotrophic lateral sclerosis.

Xiawei Dang, Lihong Zhang, Antonietta Franco, Gerald W Dorn.

Mitochondrial involvement in neurodegenerative diseases is widespread and multifactorial. Targeting mitochondrial pathology is therefore of interest. The recent development of bioactive molecules that modulate mitochondrial dynamics (fusion, fission and motility) offers a new therapeutic approach for neurodegenerative diseases with either indirect or direct mitochondrial involvement. Here, we asked: 1. Can enhanced mitochondrial fusion and motility improve secondary mitochondrial pathology in SOD1 mutant amyotrophic lateral sclerosis (ALS)? And: 2. What is the impact of enhancing mitochondria fitness on in vivo manifestations of SOD1 mutant ALS? We observed that small molecule mitofusin activators corrected mitochondrial fragmentation, depolarization and dysmotility in genetically diverse ALS patient reprogrammed motor neurons and fibroblasts, and in motor neurons, sensory neurons and fibroblasts from SOD1 G93A mice. Continuous, but not intermittent, pharmacologic mitofusin activation delayed phenotype progression and lethality in SOD1 G93A mice, reducing neuron loss and improving neuromuscular connectivity. Mechanistically, mitofusin activation increased mitochondrial motility, fitness and residency within neuromuscular synapses, reduced mitochondrial ROS production, and diminished apoptosis in SOD1 mutant neurons. These benefits were accompanied by improved mitochondrial respiratory coupling, despite characteristic SOD1 mutant ALS-associated downregulation of mitochondrial respiratory complexes. Targeting mitochondrial dysdynamism is a promising approach to alleviate pathology caused by secondary mitochondrial dysfunction in some neurodegenerative diseases.

DOI: https://doi.org/10.1093/hmg/ddac287
Food Sci Anim Resour. 2022 Nov;42(6): 981-995

Animal Models of Cognitive Deficits for Probiotic Treatment.

Oh Yun Kwon, Seung Ho Lee.

  Cognitive dysfunction is a common symptom of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, and is known to be caused by the structural and functional loss of neurons. Many natural agents that can improve cognitive function have been developed and assessed for efficacy using various cognitive deficit animal models. As the gut environment is known to be closely connected to brain function, probiotics are attracting attention as an effective treatment target that can prevent and mitigate cognitive deficits as a result of neurodegenerative diseases. Thus, the objective of this review is to provide useful information about the types and characteristics of cognitive deficit animal models, which can be used to evaluate the anti-cognitive effects of probiotics. In addition, this work reviewed recent studies describing the effects and treatment conditions of probiotics on cognitive deficit animal models. Collectively, this review shows the potential of probiotics as edible natural agents that can mitigate cognitive impairment. It also provides useful information for the design of probiotic treatments for cognitive deficit patients in future clinical studies.

Keywords:  cognitive deficits; gut-brain axis; neurodegenerative disease; probiotics

DOI:  https://doi.org/10.5851/kosfa.2022.e45
Int J Mol Sci. 2022 Nov 08. pii: 13665. [Epub ahead of print]23(22):

What Are the Key Gut Microbiota Involved in Neurological Diseases? A Systematic Review.

Bruno Bonnechère, Najaf Amin, Cornelia van Duijn.

  There is a growing body of evidence highlighting there are significant changes in the gut microbiota composition and relative abundance in various neurological disorders. We performed a systematic review of the different microbiota altered in a wide range of neurological disorders (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis, and stroke). Fifty-two studies were included representing 5496 patients. At the genus level, the most frequently involved microbiota are Akkermansia, Faecalibacterium, and Prevotella. The overlap between the pathologies was strongest for MS and PD, sharing eight genera (Akkermansia, Butyricicoccus, Bifidobacterium, Coprococcus, Dorea, Faecalibacterium, Parabacteroides, and Prevotella) and PD and stroke, sharing six genera (Enterococcus, Faecalibacterium, Lactobacillus, Parabacteroides, Prevotella, and Roseburia). The identification signatures overlapping for AD, PD, and MS raise the question of whether these reflect a common etiology or rather common consequence of these diseases. The interpretation is hampered by the low number and low power for AD, ALS, and stroke with ample opportunity for false positive and false negative findings.

Keywords:  Alzheimer’s disease; Parkinson’s disease; atrophic lateral sclerosis; gut microbiome; multiple sclerosis; stroke

DOI:  https://doi.org/10.3390/ijms232213665
Int Rev Neurobiol. 2022 ;pii: S0074-7742(22)00045-9. [Epub ahead of print]167 185-215

Role of the gut microbiome in multiple sclerosis: From etiology to therapeutics.

Shailesh K Shahi, Meeta Yadav, Sudeep Ghimire, Ashutosh K Mangalam.

  Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS that affects around one million people in the United States. Predisposition or protection from this disease is linked with both genetic and environmental factors. In recent years, gut microbiome has emerged as an important environmental factor in the pathobiology of MS. The gut microbiome supports various physiologic functions, including the development and maintenance of the host immune system, the perturbation of which is known as dysbiosis and has been linked with multiple diseases including MS. We and others have shown that people with MS (PwMS) have gut dysbiosis that is characterized by specific gut bacteria being enriched or depleted. Consequently, there is an emphasis on determining the mechanism(s) through which gut bacteria and/or their metabolites alter the course of MS through their ability to provide protection, predispose individuals, or promote disease progression. Improving our understanding of these mechanisms will allow us to harness the enormous potential of the gut microbiome as a diagnostic and/or therapeutic agent. In this chapter, we will discuss current advances in microbiome research in the context of MS, including a review of specific bacteria that are currently linked with this disease, potential mechanisms of disease pathogenesis, and the utility of microbiome-based therapy for PwMS.

Keywords:  BRUGS; Dysbiosis; Gut microbiota; Multiple sclerosis; Probiotics

DOI:  https://doi.org/10.1016/bs.irn.2022.06.001
Metabolites. 2022 Nov 17. pii: 1126. [Epub ahead of print]12(11):

Low-Carbohydrate High-Fat Diet: A SWOC Analysis.

Dena Nuwaylati, Basmah Eldakhakhny, Abdulhadi Bima, Hussein Sakr, Ayman Elsamanoudy.

  Insulin resistance (IR) plays a role in the pathogenesis of many diseases, such as type 2 diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, obesity, and neurodegenerative diseases, including Alzheimer's disease. The ketogenic diet (KD) is a low-carbohydrate/high-fat diet that arose in the 1920s as an effective treatment for seizure control. Since then, the KD has been studied as a therapeutic approach for various IR-related disorders with successful results. To date, the use of the KD is still debatable regarding its safety. Some studies have acknowledged its usefulness, while others do not recommend its long-term implementation. In this review, we applied a SWOC (Strengths, Weaknesses, Opportunities, and Challenges) analysis that revealed the positive, constructive strengths of the KD, its potential complications, different conditions that can make used for it, and the challenges faced by both physicians and subjects throughout a KD. This SWOC analysis showed that the KD works on the pathophysiological mechanism of IR-related disorders such as chronic inflammation, oxidative stress and mitochondrial stress. Furthermore, the implementation of the KD as a potential adjuvant therapy for many diseases, including cancer, neurodegenerative disorders, polycystic ovary syndrome, and pain management was proven. On the other hand, the short and long-term possible undesirable KD-related effects, including nutritional deficiencies, growth retardation and nephrolithiasis, should be considered and strictly monitored. Conclusively, this review provides a context for decision-makers, physicians, researchers, and the general population to focus on this dietary intervention in preventing and treating diseases. Moreover, it draws the attention of scientists and physicians towards the opportunities and challenges associated with the KD that requires attention before KD initiation.

Keywords:  high-fat diet; ketogenic diet; low-carbohydrate diet; nutritional ketosis; obesity; weight loss

DOI:  https://doi.org/10.3390/metabo12111126
Int J Mol Sci. 2022 Nov 20. pii: 14417. [Epub ahead of print]23(22):

The Role of Insulin Signaling in Hippocampal-Related Diseases: A Focus on Alzheimer's Disease.

Qi Liu, Zixu Wang, Jing Cao, Yulan Dong, Yaoxing Chen.

  Alzheimer's disease (AD) is a global concern and has become a major public health event affecting human health. Insulin is a metabolic hormone secreted mainly by the peripheral tissue pancreas. In recent years, more and more evidence has proved that insulin regulates various functions of the brain. The hippocampus, one of the earliest brain regions affected by AD, is widely distributed with insulin receptors. Studies have shown that type 2 diabetes mellitus, characterized by insulin resistance, is closely related to AD, which has drawn extensive attention to the relationship between hippocampal insulin signaling and AD. Therefore, we provide an overview of intranasal insulin administration on memory and its underlying mechanism. We also highlight the molecular link between hippocampal insulin resistance and AD and provide a theoretical basis for finding new therapeutic targets for AD in clinical practice.

Keywords:  hippocampus; insulin resistance; memory impairment; type 2 diabetes mellitus

DOI:  https://doi.org/10.3390/ijms232214417
Int J Mol Sci. 2022 Nov 16. pii: 14188. [Epub ahead of print]23(22):

Neurodegenerative Diseases: From Dysproteostasis, Altered Calcium Signalosome to Selective Neuronal Vulnerability to AAV-Mediated Gene Therapy.

Tam T Quach, Harrison J Stratton, Rajesh Khanna, Sabrina Mackey-Alfonso, Nicolas Deems, Jérome Honnorat, Kathrin Meyer, Anne-Marie Duchemin.

  Despite intense research into the multifaceted etiology of neurodegenerative diseases (ND), they remain incurable. Here we provide a brief overview of several major ND and explore novel therapeutic approaches. Although the cause (s) of ND are not fully understood, the accumulation of misfolded/aggregated proteins in the brain is a common pathological feature. This aggregation may initiate disruption of Ca++ signaling, which is an early pathological event leading to altered dendritic structure, neuronal dysfunction, and cell death. Presently, ND gene therapies remain unidimensional, elusive, and limited to modifying one pathological feature while ignoring others. Considering the complexity of signaling cascades in ND, we discuss emerging therapeutic concepts and suggest that deciphering the molecular mechanisms involved in dendritic pathology may broaden the phenotypic spectrum of ND treatment. An innovative multiplexed gene transfer strategy that employs silencing and/or over-expressing multiple effectors could preserve vulnerable neurons before they are lost. Such therapeutic approaches may extend brain health span and ameliorate burdensome chronic disease states.

Keywords:  CRMP3/DPYSL4; calcium signaling; dendritic dystrophy; dysproteostasis; gene therapy; neurodegeneration; neuronal vulnerability

DOI:  https://doi.org/10.3390/ijms232214188
Biomolecules. 2022 Nov 11. pii: 1676. [Epub ahead of print]12(11):

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer's Disease and Identifying Promising Drug Targets.

Zdeněk Fišar.

  Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer's disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.

Keywords:  Alzheimer’s disease; amyloid beta; drug; mitochondria; tau protein

DOI:  https://doi.org/10.3390/biom12111676
Int J Mol Sci. 2022 Nov 12. pii: 13970. [Epub ahead of print]23(22):

Amyloidogenesis: What Do We Know So Far?

Zeina Alraawi, Nayan Banerjee, Srujana Mohanty, Thallapuranam Krishnaswamy Suresh Kumar.

  The study of protein aggregation, and amyloidosis in particular, has gained considerable interest in recent times. Several neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's (PD) show a characteristic buildup of proteinaceous aggregates in several organs, especially the brain. Despite the enormous upsurge in research articles in this arena, it would not be incorrect to say that we still lack a crystal-clear idea surrounding these notorious aggregates. In this review, we attempt to present a holistic picture on protein aggregation and amyloids in particular. Using a chronological order of discoveries, we present the case of amyloids right from the onset of their discovery, various biophysical techniques, including analysis of the structure, the mechanisms and kinetics of the formation of amyloids. We have discussed important questions on whether aggregation and amyloidosis are restricted to a subset of specific proteins or more broadly influenced by the biophysiochemical and cellular environment. The therapeutic strategies and the significant failure rate of drugs in clinical trials pertaining to these neurodegenerative diseases have been also discussed at length. At a time when the COVID-19 pandemic has hit the globe hard, the review also discusses the plausibility of the far-reaching consequences posed by the virus, such as triggering early onset of amyloidosis. Finally, the application(s) of amyloids as useful biomaterials has also been discussed briefly in this review.

Keywords:  Aβ peptide; COVID-19 and amyloidosis; amyloid precursor protein; amyloid related diseases; amyloid structure analysis; amyloids; fibril formation; physical techniques in amyloid analysis; protein aggregation

DOI:  https://doi.org/10.3390/ijms232213970
Signal Transduct Target Ther. 2022 Nov 23. 7(1): 378

Copper homeostasis and cuproptosis in health and disease.

Liyun Chen, Junxia Min, Fudi Wang.

As an essential micronutrient, copper is required for a wide range of physiological processes in virtually all cell types. Because the accumulation of intracellular copper can induce oxidative stress and perturbing cellular function, copper homeostasis is tightly regulated. Recent studies identified a novel copper-dependent form of cell death called cuproptosis, which is distinct from all other known pathways underlying cell death. Cuproptosis occurs via copper binding to lipoylated enzymes in the tricarboxylic acid (TCA) cycle, which leads to subsequent protein aggregation, proteotoxic stress, and ultimately cell death. Here, we summarize our current knowledge regarding copper metabolism, copper-related disease, the characteristics of cuproptosis, and the mechanisms that regulate cuproptosis. In addition, we discuss the implications of cuproptosis in the pathogenesis of various disease conditions, including Wilson's disease, neurodegenerative diseases, and cancer, and we discuss the therapeutic potential of targeting cuproptosis.

DOI: https://doi.org/10.1038/s41392-022-01229-y
Biomedicines. 2022 Nov 14. pii: 2922. [Epub ahead of print]10(11):

Interdisciplinary Approaches to Deal with Alzheimer's Disease-From Bench to Bedside: What Feasible Options Do Already Exist Today?

Irene Ablinger, Katharina Dressel, Thea Rott, Anna Andrea Lauer, Michael Tiemann, João Pedro Batista, Tim Taddey, Heike Sabine Grimm, Marcus Otto Walter Grimm.

  Alzheimer's disease is one of the most common neurodegenerative diseases in the western population. The incidence of this disease increases with age. Rising life expectancy and the resulting increase in the ratio of elderly in the population are likely to exacerbate socioeconomic problems. Alzheimer's disease is a multifactorial disease. In addition to amyloidogenic processing leading to plaques, and tau pathology, but also other molecular causes such as oxidative stress or inflammation play a crucial role. We summarize the molecular mechanisms leading to Alzheimer's disease and which potential interventions are known to interfere with these mechanisms, focusing on nutritional approaches and physical activity but also the beneficial effects of cognition-oriented treatments with a focus on language and communication. Interestingly, recent findings also suggest a causal link between oral conditions, such as periodontitis or edentulism, and Alzheimer's disease, raising the question of whether dental intervention in Alzheimer's patients can be beneficial as well. Unfortunately, all previous single-domain interventions have been shown to have limited benefit to patients. However, the latest studies indicate that combining these efforts into multidomain approaches may have increased preventive or therapeutic potential. Therefore, as another emphasis in this review, we provide an overview of current literature dealing with studies combining the above-mentioned approaches and discuss potential advantages compared to monotherapies. Considering current literature and intervention options, we also propose a multidomain interdisciplinary approach for the treatment of Alzheimer's disease patients that synergistically links the individual approaches. In conclusion, this review highlights the need to combine different approaches in an interdisciplinary manner, to address the future challenges of Alzheimer's disease.

Keywords:  Alzheimer’s disease; cognition-oriented treatment; communication; interdisciplinary approaches; multidomain intervention; multimodal intervention; nutritional approaches; oral health; physical activity; socioeconomic factors

DOI:  https://doi.org/10.3390/biomedicines10112922
Int Rev Neurobiol. 2022 ;pii: S0074-7742(22)00138-6. [Epub ahead of print]167 xi-xvi

Introduction: Unraveling the complex contributions of indigenous microbes to neurological health and disease.

Timothy R Sampson.

  The complex interactions between the human body and its indigenous microbes have come into focus as key mediators of neurological health. With both established and emerging association studies, alterations to the gut microbiome are observed to co-occur with many neurological diseases. Whether these associations are due to microbiome-mediated contributions to human health or an effect of the neurological disease itself is largely unknown across conditions. Here, we have collected contributions from a broad group of experts that highlight gut microbiome impacts across numerous neurological conditions. Ranging from neurodevelopmental disorders, to Parkinson's disease, Alzheimer's disease, epilepsy, traumatic injury, and amyotrophic lateral sclerosis, among others, we hope to provide a clearer picture of how our indigenous microbes impact neurological health. The study of these indigenous microbes will continue to reveal critical mechanisms that may 1 day be exploited for therapeutic benefits against these recalcitrant diseases.

Keywords:  Gut–brain; Holobiont; Hologenome; Microbiome; Neurodegenerative disease; Neurological disease

DOI:  https://doi.org/10.1016/S0074-7742(22)00138-6
J Clin Med. 2022 Nov 14. pii: 6742. [Epub ahead of print]11(22):

Therapeutic Potential of Targeting Mitochondria for Alzheimer's Disease Treatment.

Anna Atlante, Giuseppina Amadoro, Valentina Latina, Daniela Valenti.

  Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, is characterized by memory and cognitive impairment and by the accumulation in the brain of abnormal proteins, more precisely beta-amyloid (β-amyloid or Aβ) and Tau proteins. Studies aimed at researching pharmacological treatments against AD have focused precisely on molecules capable, in one way or another, of preventing/eliminating the accumulations of the aforementioned proteins. Unfortunately, more than 100 years after the discovery of the disease, there is still no effective therapy in modifying the biology behind AD and nipping the disease in the bud. This state of affairs has made neuroscientists suspicious, so much so that for several years the idea has gained ground that AD is not a direct neuropathological consequence taking place downstream of the deposition of the two toxic proteins, but rather a multifactorial disease, including mitochondrial dysfunction as an early event in the pathogenesis of AD, occurring even before clinical symptoms. This is the reason why the search for pharmacological agents capable of normalizing the functioning of these subcellular organelles of vital importance for nerve cells is certainly to be considered a promising approach to the design of effective neuroprotective drugs aimed at preserving this organelle to arrest or delay the progression of the disease. Here, our intent is to provide an updated overview of the mitochondrial alterations related to this disorder and of the therapeutic strategies (both natural and synthetic) targeting mitochondrial dysfunction.

Keywords:  Alzheimer; mitochondrial bioenergetics; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; neurodegeneration; therapeutic strategies

DOI:  https://doi.org/10.3390/jcm11226742
Polymers (Basel). 2022 Nov 18. pii: 5014. [Epub ahead of print]14(22):

The Alterations and Roles of Glycosaminoglycans in Human Diseases.

Qingchi Wang, Lianli Chi.

  Glycosaminoglycans (GAGs) are a heterogeneous family of linear polysaccharides which are composed of a repeating disaccharide unit. They are also linked to core proteins to form proteoglycans (PGs). GAGs/PGs are major components of the cell surface and the extracellular matrix (ECM), and they display critical roles in development, normal function, and damage response in the body. Some properties (such as expression quantity, molecular weight, and sulfation pattern) of GAGs may be altered under pathological conditions. Due to the close connection between these properties and the function of GAGs/PGs, the alterations are often associated with enormous changes in the physiological/pathological status of cells and organs. Therefore, these GAGs/PGs may serve as marker molecules of disease. This review aimed to investigate the structural alterations and roles of GAGs/PGs in a range of diseases, such as atherosclerosis, cancer, diabetes, neurodegenerative disease, and virus infection. It is hoped to provide a reference for disease diagnosis, monitoring, prognosis, and drug development.

Keywords:  ECM remodeling; chondroitin sulfate; dermatan sulfate; glycosaminoglycan; heparan sulfate; human disease

DOI:  https://doi.org/10.3390/polym14225014
Nutrients. 2022 Nov 12. pii: 4791. [Epub ahead of print]14(22):

Iron Supplementation in Pregnancy and Risk of Gestational Diabetes: A Narrative Review.

Clive J Petry.

  Pregnant women frequently supplement their diets with iron to treat any cryptic anemia, on the assumption that if anemia is not present, there will be no negative consequences. However, in women who are already iron-replete, it has been suggested that this can lead to iron overload and an increased risk of certain pregnancy complications. One such complication is gestational diabetes. Fourteen clinical trials, case-control or cohort studies (found using Pubmed/Scopus/Web of Science) have investigated links between iron supplementation in pregnancy and risk of gestational diabetes, several of them finding significant associations with increased risk. Potential mechanisms include increased oxidative stress leading to insulin resistance and inadequate compensatory insulin secretion. Current evidence suggests that dietary supplementation with iron in pregnancy may increase a pregnant woman's chance of developing gestational diabetes, although available evidence is somewhat contradictory, and the magnitude of any increased risk appears relatively small. Meta-analyses have suggested the presence of significant heterogeneity in results between studies, urging a degree of caution in interpreting these results. It is currently suggested that advice to pregnant women about whether to supplement their diets with iron or not should consider both their current iron status and their other established risk factors for gestational diabetes.

Keywords:  diabetes; dietary supplementation; ferritin; insulin resistance; insulin secretion; iron; micronutrients; oxidative stress; pregnancy

DOI:  https://doi.org/10.3390/nu14224791
Genes (Basel). 2022 Nov 17. pii: 2142. [Epub ahead of print]13(11):

Multi-Omics Nutritional Approaches Targeting Metabolic-Associated Fatty Liver Disease.

Omar Ramos-Lopez.

  Currently, metabolic-associated fatty liver disease (MAFLD) is a leading global cause of chronic liver disease, and is expected to become one of the most common indications of liver transplantation. MAFLD is associated with obesity, involving multiple mechanisms such as alterations in lipid metabolism, insulin resistance, hyperinflammation, mitochondrial dysfunction, cell apoptosis, oxidative stress, and extracellular matrix formation. However, the onset and progression of MAFLD is variable among individuals, being influenced by intrinsic (personal) and external environmental factors. In this context, sequence structural variants across the human genome, epigenetic phenomena (i.e., DNA methylation, histone modifications, and long non-coding RNAs) affecting gene expression, gut microbiota dysbiosis, and metabolomics/lipidomic fingerprints may account for differences in MAFLD outcomes through interactions with nutritional features. This knowledge may contribute to gaining a deeper understanding of the molecular and physiological processes underlying MAFLD pathogenesis and phenotype heterogeneity, as well as facilitating the identification of biomarkers of disease progression and therapeutic targets for the implementation of tailored nutritional strategies. This comprehensive literature review highlights the potential of nutrigenetic, nutriepigenetic, nutrimetagenomic, nutritranscriptomics, and nutrimetabolomic approaches for the prevention and management of MAFLD in humans through the lens of precision nutrition.

Keywords:  MAFLD; metabolomics; metagenomics; nutriepigenetics; nutrigenetics; nutrigenomics; precision nutrition; proteomics

DOI:  https://doi.org/10.3390/genes13112142
Front Aging. 2022 ;3 1043300

Prohibitins in neurodegeneration and mitochondrial homeostasis.

Jesus Fernandez-Abascal, Marta Artal-Sanz.

  The incidence of age-related neurodegenerative disorders has risen with the increase of life expectancy. Unfortunately, the diagnosis of such disorders is in most cases only possible when the neurodegeneration status is already advanced, and symptoms are evident. Although age-related neurodegeneration is a common phenomenon in living animals, the cellular and molecular mechanisms behind remain poorly understood. Pathways leading to neurodegeneration usually diverge from a common starting point, mitochondrial stress, which can serve as a potential target for early diagnosis and treatments. Interestingly, the evolutionarily conserved mitochondrial prohibitin (PHB) complex is a key regulator of ageing and metabolism that has been associated with neurodegenerative diseases. However, its role in neurodegeneration is still not well characterized. The PHB complex shows protective or toxic effects in different genetic and physiological contexts, while mitochondrial and cellular stress promote both up and downregulation of PHB expression. With this review we aim to shed light into the complex world of PHB's function in neurodegeneration by putting together the latest advances in neurodegeneration and mitochondrial homeostasis associated with PHB. A better understanding of the role of PHB in neurodegeneration will add knowledge to neuron deterioration during ageing and help to identify early molecular markers of mitochondrial stress. This review will deepen our understanding of age-related neurodegeneration and provide questions to be addressed, relevant to human health and to improve the life quality of the elderly.

Keywords:  aging; mitochondria; nervous system; neurodegeneration; prohibitin (PHB)

DOI:  https://doi.org/10.3389/fragi.2022.1043300
J Clin Med. 2022 Nov 12. pii: 6702. [Epub ahead of print]11(22):

Retinal Microvascular Dysfunction Occurs Early and Similarly in Mild Alzheimer's Disease and Primary-Open Angle Glaucoma Patients.

Stephanie Mroczkowska, Hala Shokr, Alexandra Benavente-Pérez, Anil Negi, Peter Bentham, Doina Gherghel.

  PURPOSE: To assess the similarities and differences in retinal microvascular function between mild Alzheimer's disease (AD) patients, early-stage primary open angle glaucoma (POAG) patients and healthy controls.METHODS: Retinal vessel reactivity to flickering light was assessed in 10 AD, 19 POAG and 20 healthy age matched control patients by means of dynamic retinal vessel analysis (DVA, IMEDOS, GmbH, Jena, Germany) according to an established protocol. All patients additionally underwent BP measurements and blood analysis for glucose and lipid metabolism markers.
RESULTS: AD and POAG patients demonstrated comparable alterations in retinal artery reactivity, in the form of an increased arterial reaction time (RT) to flicker light on the final flicker cycle (p = 0.009), which was not replicated by healthy controls (p > 0.05). Furthermore, the sequential changes in RT on progressing from flicker one to flicker three were found to differ between healthy controls and the two disease groups (p = 0.001).
CONCLUSION: AD and POAG patients demonstrate comparable signs of vascular dysfunction in their retinal arteries at the early stages of their disease process. This provides support for the concept of a common underlying vascular aetiology in these two neurodegenerative diseases.

Keywords:  Alzheimer’s disease; glaucoma; retinal vessel analysis; vascular dysfunction

DOI:  https://doi.org/10.3390/jcm11226702