bims-metalz 2023-04-16 papers

bims-metalz

Biomed News

on Metabolic causes of Alzheimer’s disease

Issue of 2023–04–16
eleven papers selected by
Mikaila Chetty, Goa University

Molecular systems biology approaches to investigate mechanisms of gut-brain communication in neurological diseases.
Enteric Glia and Brain Astroglia: Complex Communication in Health and Disease along the Gut-Brain Axis.
Nutrition in Alzheimer's disease: a review of an underappreciated pathophysiological mechanism.
Lactobacillus plantarum CCFM405 against Rotenone-Induced Parkinson's Disease Mice via Regulating Gut Microbiota and Branched-Chain Amino Acids Biosynthesis.
Early-Life Lead Exposure: Risks and Neurotoxic Consequences.
Hakuna MAM-Tata: Investigating the role of mitochondrial-associated membranes in ALS.
A tailored tetravalent peptide displays dual functions to inhibit amyloid β production and aggregation.
Mitochondrion: A bridge linking aging and degenerative diseases.
The Role of Rab Proteins in Mitophagy: Insights into Neurodegenerative Diseases.
Dityrosine cross-linking and its potential roles in Alzheimer's disease.
The Role of miR-128 in Neurodegenerative Diseases.

Eur J Neurol. 2023 Apr 10.

Molecular systems biology approaches to investigate mechanisms of gut-brain communication in neurological diseases.

Vandemoortele Boris, Vermeirssen Vanessa.

  While the incidence of neurological disease is increasing worldwide, treatment remains mostly limited to symptom management. The gut-brain axis, which encompasses the communication routes between microbiota, gut, and brain, has emerged as a crucial area of investigation for identifying new preventive and therapeutic targets in neurological disease. Due to the inter-organ, systemic nature of the gut-brain axis, together with the multitude of biomolecules and microbial species involved, molecular systems biology approaches are required to accurately investigate the mechanisms of gut-brain communication. High-throughput omics profiling, together with computational methodologies such as dimensionality reduction or clustering, machine learning, network inference and genome-scale metabolic models, allow to discover novel biomarkers and elucidate mechanistic insights. In this review, we introduce the general concepts of experimental and computational methodologies for gut-brain axis research and discuss their applications, mainly in human cohorts. We further highlight important aspects concerning rational study design, sampling procedures and data modalities relevant for gut-brain communication, strengths and limitations of methodological approaches and some future perspectives. In conclusion, we review how multi-omics analysis, together with advanced data mining, are essential to functionally characterize the gut-brain axis in neurological disease and finally put forward novel preventive or therapeutic strategies.

Keywords:  biomarkers; metabolites; microbiota; multi-omics; networks

DOI:  https://doi.org/10.1111/ene.15819
Neuroscientist. 2023 Apr 13. 10738584231163460

Enteric Glia and Brain Astroglia: Complex Communication in Health and Disease along the Gut-Brain Axis.

Vanessa D'Antongiovanni, Carolina Pellegrini, Luca Antonioli, Chiara Ippolito, Cristina Segnani, Laura Benvenuti, Antonio D'Amati, Mariella Errede, Daniela Virgintino, Matteo Fornai, Nunzia Bernardini.

  Several studies have provided interesting evidence about the role of the bidirectional communication between the gut and brain in the onset and development of several pathologic conditions, including inflammatory bowel diseases (IBDs), neurodegenerative diseases, and related comorbidities. Indeed, patients with IBD can experience neurologic disorders, including depression and cognitive impairment, besides typical intestinal symptoms. In parallel, patients with neurodegenerative disease, such as Parkinson disease and Alzheimer disease, are often characterized by the occurrence of functional gastrointestinal disorders. In this context, enteric glial cells and brain astrocytes are emerging as pivotal players in the initiation/maintenance of neuroinflammatory responses, which appear to contribute to the alterations of intestinal and neurologic functions observed in patients with IBD and neurodegenerative disorders. The present review was conceived to provide a comprehensive and critical overview of the available knowledge on the morphologic, molecular, and functional changes occurring in the enteric glia and brain astroglia in IBDs and neurologic disorders. In addition, our intent is to identify whether such alterations could represent a common denominator involved in the onset of comorbidities associated with the aforementioned disorders. This might help to identify putative targets useful to develop novel pharmacologic approaches for the therapeutic management of such disturbances.

Keywords:  Alzheimer disease; IBD; Parkinson disease; astrocytes; enteric glial cells; gut-brain axis

DOI:  https://doi.org/10.1177/10738584231163460
Sci China Life Sci. 2023 Apr 07.

Nutrition in Alzheimer's disease: a review of an underappreciated pathophysiological mechanism.

Jiwei Jiang, Hanping Shi, Shirui Jiang, Anxin Wang, Xinying Zou, Yanli Wang, Wenyi Li, Yuan Zhang, Mengfan Sun, Qiwei Ren, Jun Xu.

  Alzheimer's disease (AD) is the leading cause of dementia in older individuals and is an escalating challenge to global public health. Pharmacy therapy of AD is one of the well-funded areas; however, little progress has been made due to the complex pathogenesis. Recent evidence has demonstrated that modifying risk factors and lifestyle may prevent or delay the incidence of AD by 40%, which suggests that the management should pivot from single pharmacotherapy toward a multipronged approach because AD is a complex and multifaceted disease. Recently, the gut-microbiota-brain axis has gained tremendous traction in the pathogenesis of AD through bidirectional communication with multiple neural, immune, and metabolic pathways, providing new insights into novel therapeutic strategies. Dietary nutrition is an important and profound environmental factor that influences the composition and function of the microbiota. The Nutrition for Dementia Prevention Working Group recently found that dietary nutrition can affect cognition in AD-related dementia directly or indirectly through complex interactions of behavioral, genetic, systemic, and brain factors. Thus, considering the multiple etiologies of AD, nutrition represents a multidimensional factor that has a profound effect on AD onset and development. However, mechanistically, the effect of nutrition on AD is uncertain; therefore, optimal strategies or the timing of nutritional intervention to prevent or treat AD has not been established.Thus, this review summarizes the current state of knowledge concerning nutritional disorders, AD patient and caregiver burden, and the roles of nutrition in the pathophysiology of AD. We aim to emphasize knowledge gaps to provide direction for future research and to establish optimal nutrition-based intervention strategies for AD.

Keywords:  Alzheimer’s disease; brain-gut axis; diet; metabolism; nutrition; pathogenesis

DOI:  https://doi.org/10.1007/s11427-022-2276-6
Nutrients. 2023 Apr 01. pii: 1737. [Epub ahead of print]15(7):

Lactobacillus plantarum CCFM405 against Rotenone-Induced Parkinson's Disease Mice via Regulating Gut Microbiota and Branched-Chain Amino Acids Biosynthesis.

Chuanqi Chu, Leilei Yu, Yiwen Li, Hang Guo, Qixiao Zhai, Wei Chen, Fengwei Tian.

  Recent studies have demonstrated that disturbances in the gut microbiota and microbiota -derived metabolites contribute to the pathogenesis of Parkinson's disease (PD), suggesting that probiotic treatments that restore them may delay disease progression. This study aimed to examine the attenuating efficacy of L. plantarum CCFM405 and the potential mechanisms in mice with rotenone-induced PD. Our results indicate that L. plantarum CCFM405 ameliorated rotenone-induced motor deficits and constipation, decreased dopaminergic neuronal death, reduced intestinal inflammation and neuroinflammation, and raised dopamine levels, 5-HT, and associated metabolites in the striatal region of the brain in mice with PD. Sequencing of 16S rRNA from fecal microbiota revealed that L. plantarum CCFM405 normalized the gut bacterial composition in mice with PD, as evidenced by the increased relative abundance of the following genus, Bifidobacterium, Turicibacter, and Faecalibaculum, and decreased relative abundance of Alistipes, Bilophila, Akkermansia, and Escherichia-Shigella. The PICRUSt-predicted gut microbiota function revealed that L. plantarum CCFM405 enhanced the biosynthesis of amino acid pathways, particularly valine, leucine, and isoleucine (branched-chain amino acids, BCAAs). A non-metabolomic analysis of the serum and feces showed that L. plantarum CCFM405 markedly increased the levels of BCAAs. Pathway enrichment analysis based on the KEGG database further suggested that L. plantarum CCFM405 supplementation can promote BCAAs biosynthesis. Collectively, L. plantarum CCFM405 can help to prevent rotenone-induced PD by modulating the gut microbiota-metabolite axis. BCAAs may play a dominant role in L. plantarum CCFM405-associated neuroprotection in PD mice. This probiotic could be utilized as a potential food supplement in the management of PD.

Keywords:  Lactobacillus plantarum; Parkinson’s disease; branched amino acid; gut–brain axis

DOI:  https://doi.org/10.3390/nu15071737
Curr Med Chem. 2023 Apr 09.

Early-Life Lead Exposure: Risks and Neurotoxic Consequences.

Geir Bjørklund, Torsak Tippairote, Tony Hangan, Salvatore Chirumbolo, Massimiliano Peana.

  Lead (Pb) does not have any biological function in a human, and there is likely no safe level of Pb in the human body. The Pb exposure impacts are a global concern for their potential neurotoxic consequences. Despite decreasing both the environmental Pb levels and the average blood Pb levels in the survey populations, the lifetime redistribution from the tissues-stored Pb still poses neurotoxic risks from the low-level exposure in later life. The growing fetus and children hold their innate high-susceptible to these Pb-induced neurodevelopmental and neurobehavioral effects. This article aims to evaluate the cumulative studies and insights on the topic of Pb neurotoxicology while assessing the emerging trends in the field. The Pb-induced neurochemical and neuro-immunological mechanisms are likely responsible for the high-level Pb exposure with the neurodevelopmental and neurobehavioral impacts at the initial stages. Early-life Pb exposure can still produce neurodegenerative consequences in later life due to the altered epigenetic imprints and the ongoing endogenous Pb exposure. Several mechanisms contribute to the Pb-induced neurotoxic impacts, including the direct neurochemical effects, the induction of oxidative stress and inflammation through immunologic activations, and epigenetic alterations. Furthermore, the individual nutritional status, such as macro-, micro-, or antioxidant nutrients, can significantly influence the neurotoxic impacts even at low-level exposure to Pb. The prevention of early-life Pb exposure is, therefore, the critical determinant for alleviating various Pb-induced neurotoxic impacts across the different age groups.

Keywords:  epigenetic alterations; lead; low-level exposure; neurobehavioral; neurodegenerative; neurodevelopmental; neurotoxic

DOI:  https://doi.org/10.2174/0929867330666230409135310
Biochim Biophys Acta Mol Basis Dis. 2023 Apr 10. pii: S0925-4439(23)00082-0. [Epub ahead of print] 166716

Hakuna MAM-Tata: Investigating the role of mitochondrial-associated membranes in ALS.

Anna Fernàndez Bernal, Natàlia Mota, Reinald Pamplona, Estela Area-Gomez, Manuel Portero-Otin.

  Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive motor neuron (MN) death. Despite significant heterogeneity in pathogenic and clinical terms, MN demise ultimately unifies patients. Across the many disturbances in neuronal biology present in the disease and its models, two common trends are loss of calcium homeostasis and dysregulations in lipid metabolism. Since both mitochondria and endoplasmic reticulum (ER) are essential in these functions, their intertwin through the so-called mitochondrial-associated membranes (MAMs) should be relevant in this disease. In this review, we present a short overview of MAMs functional aspects and how its dysfunction could explain a substantial part of the cellular disarrangements in ALS's natural history. MAMs are hubs for lipid synthesis, integrating glycerophospholipids, sphingolipids, and cholesteryl ester metabolism. These lipids are essential for membrane biology, so there should be a close coupling to cellular energy demands, a role that MAMs may partially fulfill. Not surprisingly, MAMs are also host part of calcium signaling to mitochondria, so their impairment could lead to mitochondrial dysfunction, affecting oxidative phosphorylation and enhancing the vulnerability of MNs. We present data supporting that MAMs' maladaptation could be essential to MNs' vulnerability in ALS.

Keywords:  Calcium metabolism; Lipid synthesis; Mitochondria; Neurodegeneration; TDP-43

DOI:  https://doi.org/10.1016/j.bbadis.2023.166716
Commun Biol. 2023 04 08. 6(1): 383

A tailored tetravalent peptide displays dual functions to inhibit amyloid β production and aggregation.

Waka Sato, Miho Watanabe-Takahashi, Takuya Murata, Naoko Utsunomiya-Tate, Jun Motoyama, Masataka Anzai, Seiko Ishihara, Nanako Nishioka, Hina Uchiyama, Juri Togashi, Saeka Nishihara, Kiyoshi Kawasaki, Takashi Saito, Takaomi C Saido, Satoru Funamoto, Kiyotaka Nishikawa.

Inhibition of amyloid-β peptide (Aβ) accumulation in the brain is a promising approach for treatment of Alzheimer's disease (AD). Aβ is produced by β-secretase and γ-secretase in endosomes via sequential proteolysis of amyloid precursor protein (APP). Aβ and APP have a common feature to readily cluster to form multimers. Here, using multivalent peptide library screens, we identified a tetravalent peptide, LME-tet, which binds APP and Aβ via multivalent interactions. In cells, LME-tet-bound APP in the plasma membrane is transported to endosomes, blocking Aβ production through specific inhibition of β-cleavage, but not γ-cleavage. LME-tet further suppresses Aβ aggregation by blocking formation of the β-sheet conformation. Inhibitory effects are not observed with a monomeric peptide, emphasizing the significance of multivalent interactions for mediating these activities. Critically, LME-tet efficiently reduces Aβ levels in the brain of AD model mice, suggesting it may hold promise for treatment of AD.

DOI: https://doi.org/10.1038/s42003-023-04771-9
Life Sci. 2023 Apr 06. pii: S0024-3205(23)00300-4. [Epub ahead of print] 121666

Mitochondrion: A bridge linking aging and degenerative diseases.

Lanlan Zhang, Jianlong Wu, Ziguan Zhu, Yuchen He, Renpeng Fang.

  Aging is a natural process, characterized by progressive loss of physiological integrity, impaired function, and increased vulnerability to death. For centuries, people have been trying hard to understand the process of aging and find effective ways to delay it. However, limited breakthroughs have been made in anti-aging area. Since the hallmarks of aging were summarized in 2013, increasing studies focus on the role of mitochondrial dysfunction in aging and aging-related degenerative diseases, such as neurodegenerative diseases, osteoarthritis, metabolic diseases, and cardiovascular diseases. Accumulating evidence indicates that restoring mitochondrial function and biogenesis exerts beneficial effects in extending lifespan and promoting healthy aging. In this paper, we provide an overview of mitochondrial changes during aging and summarize the advanced studies in mitochondrial therapies for the treatment of degenerative diseases. Current challenges and future perspectives are proposed to provide novel and promising directions for future research.

Keywords:  Aging; Degenerative diseases; Longevity; Mitochondrion; Mitochondrion-nuclear communication; Mitophagy

DOI:  https://doi.org/10.1016/j.lfs.2023.121666
Int J Mol Sci. 2023 Mar 27. pii: 6268. [Epub ahead of print]24(7):

The Role of Rab Proteins in Mitophagy: Insights into Neurodegenerative Diseases.

Adeena Shafique, Martina Brughera, Marta Lualdi, Tiziana Alberio.

  Mitochondrial dysfunction and vesicular trafficking alterations have been implicated in the pathogenesis of several neurodegenerative diseases. It has become clear that pathogenetic pathways leading to neurodegeneration are often interconnected. Indeed, growing evidence suggests a concerted contribution of impaired mitophagy and vesicles formation in the dysregulation of neuronal homeostasis, contributing to neuronal cell death. Among the molecular factors involved in the trafficking of vesicles, Ras analog in brain (Rab) proteins seem to play a central role in mitochondrial quality checking and disposal through both canonical PINK1/Parkin-mediated mitophagy and novel alternative pathways. In turn, the lack of proper elimination of dysfunctional mitochondria has emerged as a possible causative/early event in some neurodegenerative diseases. Here, we provide an overview of major findings in recent years highlighting the role of Rab proteins in dysfunctional mitochondrial dynamics and mitophagy, which are characteristic of neurodegenerative diseases. A further effort should be made in the coming years to clarify the sequential order of events and the molecular factors involved in the different processes. A clear cause-effect view of the pathogenetic pathways may help in understanding the molecular basis of neurodegeneration.

Keywords:  Ras analog in brain (Rab); mitophagy; neurodegeneration; vesicular trafficking

DOI:  https://doi.org/10.3390/ijms24076268
Front Neurosci. 2023 ;17 1132670

Dityrosine cross-linking and its potential roles in Alzheimer's disease.

Mahmoud B Maina, Youssra K Al-Hilaly, Louise C Serpell.

  Oxidative stress is a significant source of damage that accumulates during aging and contributes to Alzheimer's disease (AD) pathogenesis. Oxidation of proteins can give rise to covalent links between adjacent tyrosines known as dityrosine (DiY) cross-linking, amongst other modifications, and this observation suggests that DiY could serve as a biomarker of accumulated oxidative stress over the lifespan. Many studies have focused on understanding the contribution of DiY to AD pathogenesis and have revealed that DiY crosslinks can be found in both Aβ and tau deposits - the two key proteins involved in the formation of amyloid plaques and tau tangles, respectively. However, there is no consensus yet in the field on the impact of DiY on Aβ and tau function, aggregation, and toxicity. Here we review the current understanding of the role of DiY on Aβ and tau gathered over the last 20 years since the first observation, and discuss the effect of this modification for Aβ and tau aggregation, and its potential as a biomarker for AD.

Keywords:  Alzheimer’s disease; amyloid-beta; dityrosine; oxidative; tau

DOI:  https://doi.org/10.3389/fnins.2023.1132670
Int J Mol Sci. 2023 Mar 23. pii: 6024. [Epub ahead of print]24(7):

The Role of miR-128 in Neurodegenerative Diseases.

Marika Lanza, Salvatore Cuzzocrea, Salvatore Oddo, Emanuela Esposito, Giovanna Casili.

  Several neurodegenerative disorders are characterized by the accumulation of misfolded proteins and are collectively known as proteinopathies. Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) represent some of the most common neurodegenerative disorders whose steady increase in prevalence is having a major socio-economic impact on our society. Multiple laboratories have reported hundreds of changes in gene expression in selective brain regions of AD, PD, and HD brains. While the mechanisms underlying these changes remain an active area of investigation, alterations in the expression of noncoding RNAs, which are common in AD, PD, and HD, may account for some of the changes in gene expression in proteinopathies. In this review, we discuss the role of miR-128, which is highly expressed in mammalian brains, in AD, PD, and HD. We highlight how alterations in miR-128 may account, at least in part, for the gene expression changes associated with proteinopathies. Indeed, miR-128 is involved, among other things, in the regulation of neuronal plasticity, cytoskeletal organization, and neuronal death, events linked to various proteinopathies. For example, reducing the expression of miR-128 in a mouse model of AD ameliorates cognitive deficits and reduces neuropathology. Overall, the data in the literature suggest that targeting miR-128 might be beneficial to mitigate the behavioral phenotype associated with these diseases.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; brain; miR-128; neurodegenerative disease

DOI:  https://doi.org/10.3390/ijms24076024