Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 16, 2024

Abstract The human gastrointestinal tract is populated with a diverse microbial community. vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect biology, including health maintenance, development, aging, disease. advent new sequencing technologies culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations shed light on microbiome–host interactions. Evidence unveiled bidirectional communication between central nervous system, referred as “microbiota–gut–brain axis”. microbiota–gut–brain axis represents an important regulator glial functions, making it actionable target ameliorate development progression neurodegenerative diseases. In this review, we discuss mechanisms As provides essential cues microglia, astrocytes, oligodendrocytes, examine communications microbiota these cells during healthy states Subsequently, diseases using metabolite-centric approach, while also examining role microbiota-related neurotransmitters hormones. Next, targeting intestinal barrier, blood–brain meninges, peripheral immune system counteract dysfunction neurodegeneration. Finally, conclude by assessing pre-clinical clinical evidence probiotics, prebiotics, fecal transplantation A thorough comprehension will foster effective therapeutic interventions for management

Language: Английский

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Progression of cerebral amyloid angiopathy: a pathophysiological framework

The Lancet Neurology, Journal Year: 2023, Volume and Issue: 22(7), P. 632 - 642

Published: May 23, 2023

Language: Английский

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Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 26, 2024

The induced pluripotent stem cell (iPSC) technology has transformed in vitro research and holds great promise to advance regenerative medicine. iPSCs have the capacity for an almost unlimited expansion, are amenable genetic engineering, can be differentiated into most somatic types. been widely applied model human development diseases, perform drug screening, develop therapies. In this review, we outline key developments iPSC field highlight immense versatility of modeling therapeutic applications. We begin by discussing pivotal discoveries that revealed potential a nucleus reprogramming led successful generation iPSCs. consider molecular mechanisms dynamics as well numerous methods available induce pluripotency. Subsequently, discuss various iPSC-based cellular models, from mono-cultures single type complex three-dimensional organoids, how these models elucidate diseases. use examples neurological disorders, coronavirus disease 2019 (COVID-19), cancer diversity disease-specific phenotypes modeled using iPSC-derived cells. also used high-throughput screening toxicity studies. Finally, process developing autologous allogeneic therapies their alleviate

Language: Английский

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Pericytes in the disease spotlight

Trends in Cell Biology, Journal Year: 2023, Volume and Issue: 34(1), P. 58 - 71

Published: July 18, 2023

Molecular and functional pericyte studies at single-cell resolution are providing new insights into long-standing questions about heterogeneity.Pericytes not identified by a single marker but instead gene expression signatures that show substantial inter-organ differences.Pericytes orchestrate precede endothelial cell responses during angiogenesis.Pericyte degeneration dysfunction, triggered the onset of some diseases, contribute to progression those diseases in both vascular non-vascular contexts.The number with dysfunction continues expand, thereby anticipating promising future for pericyte-focused therapy. Pericytes classically defined as mural cells (see Glossary) envelop endothelium small caliber blood vessels, so-called capillaries. embedded within same basement membrane (ECs) interact closely them [1.Armulik A. et al.Pericytes: developmental, physiological, pathological perspectives, problems, promises.Dev. Cell. 2011; 21: 193-215Abstract Full Text PDF PubMed Scopus (1790) Google Scholar,2.Holm al.Microvascular organotypic heterogeneity plasticity.Trends Cell Biol. 2018; 28: 302-316Abstract (63) Scholar]. By contrast, smooth muscle (vSMCs), other type, cover large arteries veins, physically separated from an intimal layer extracellular matrix (ECM). Of note, lymphatic capillaries lack pericytes under physiological conditions, although collecting vessels contain vSMCs [3.Petrova T.V. Koh G.Y. Biological functions vessels.Science. 2020; 369eaax4063Crossref (144) A fundamental function is regulate stabilization vessels. It therefore surprising loss were linked several including cancer cerebrovascular more than decade ago [4.Martin J.D. al.Normalizing tumor vessels: progress, opportunities, challenges.Annu. Rev. Physiol. 2019; 81: 505-534Crossref (242) Scholar,5.Lendahl U. al.Emerging links between neurodegenerative diseases-a special role pericytes.EMBO Rep. 20e48070Crossref (71) However, therapies have been poorly explored. Instead, most on vascular-directed therapeutic strategies ECs – central components build Emerging data are, however, changing perception mere supporting recruited final stage vessel formation essential elements early phases angiogenesis anticipate EC behavior. In addition, recent research revealing novel roles beyond their implications vasculature. Collectively, we believe these open exciting avenues approaches call broader understanding disease progression. We provide here global overview significant advances regarding our different pathobiological scenarios discuss field's current paradigms controversies. First, address associated responses. Second, evidence disease, cell-autonomous For comprehensive details biology, ontology, specific signaling pathways, refer reader importance, emerging concepts biology described following sections only studied one tissue. To avoid confusion generalizability properties, frame each considering relevant organ study. exhibit inter- intra-tissue molecular differences exert tissue-specific [2.Holm Their molecular, morphological, inextricably diverse developmental origins, modes recruitment, anatomical localization. example, nervous system (CNS) microvasculature firmly continuously invested around support barrier whereas liver pericytes, commonly referred hepatic stellate (HSCs), reside perisinusoidal space, loosely discontinuously ECs, hold unique vitamin storage capacity meet demands, distribution density variable among organs beds, CNS showing greatest pericyte-to-EC abundance. From standpoint there no can exclusively identify (Box 1), albeit emergence techniques shedding light markers functions. first atlas types brain adult mice RNA sequencing (scRNA-seq) revealed follow gradient transitional phenotypes. This occurs interface precapillary arterioles, capillaries, postcapillary venules, does continuum along arteriovenous axis (Figure 1 Box 1) [6.Vanlandewijck M. al.A zonation vasculature.Nature. 554: 475-480Crossref (876) Whether this phenotypes specifically restricted vasculature or also present beds remains be determined. Indeed, many 2 illustrates three top-ranked enriched per organ), which transporters contractile machinery [7.Muhl L. al.Single-cell analysis uncovers fibroblast criteria identification discrimination.Nat. Commun. 11: 3953Crossref (187) Another intriguing observation cross-organ Scholar,8.Muhl transcriptomic inventory murine cells.Dev. 2022; 57: 2426-2443Abstract Currently, inter-tissue behavior two main completely understood. may because greater cell-intrinsic plasticity adapt portfolio fulfill universal across tissues. contrast differences, transcription factors appears relatively conserved organs, suggesting subtypes epigenetic mechanisms Accordingly, DNA hypermethylation was recently found control alpha actin (αSMA) renal after ischemia [9.Chou Y.H. al.Methylation acute injury promotes chronic kidney disease.J. Clin. Invest. 130: 4845-4857Crossref (18) indicates methods such assay transposase-accessible chromatin (ATAC-seq) will instrumental further understand phenotypes.Box 1Unraveling identity pericytesThe challenging task. Despite ongoing efforts, consensus unambiguous identification. date all distinguish types, scRNA-seq now opportunities discern tissue specificity Scholar,71.Teuwen L.A. al.Tumor co-option probed analysis.Cell 2021; 35109253Abstract (35) Scholar,93.Baek S.H. al.Single reveals identities.Front Cardiovasc. Med. 9876591Crossref (9) The use transgenic reporter mouse models has label, trace, locate populations vivo. combination multiple lines often necessary properly discriminate perivascular Scholar, 7.Muhl 8.Muhl Mural highly plastic cells; phenotypic do Figure 1A,B text) transcriptional point view, distinct continuums cells: (i) capillary venous (SMCs), where gradually transition SMC phenotype, (ii) arterial SMCs pattern towards arteriole SMCs. resemblance venular Scholar], well classic led hypothesis transcriptionally morphologically similar Human recapitulate pattern, human evenly distributed over veins [50.Yang A.C. mediators Alzheimer's risk.Nature. 603: 885-892Crossref (117) Scholar,94.Garcia F.J. dissection 893-899Crossref (53) Unlike separation brain, discerned functionality marked solute transport (ECM) organization Unfortunately, ability predict presence limited, select few retain adequate specificity. zebrafish better alternative study genes [95.Shih al.Integrated identifies signature zebrafish.Development. 148dev200189Crossref (4) RGS5, NDUFA4L2, KNCJ8, HIGD1B, ABCC9, NOTCH3, PDGFRB currently species markers, detailed characterization when studying text).Figure 2Organotypic markers.Show full captionThis figure summarizes heart, lung, kidney, colon (upper row) (lower row). Pericyte chosen based stringent evaluation abundance, specificity, homogeneity utilizing information provided Scholar,50.Yang Scholar,82.Muhl al.The SARS-CoV-2 receptor ACE2 expressed COVID-19 research.Stem 17: 1089-1104Abstract (0) Scholar,84.Dobie R. transcriptomics mesenchyme fibrosis.Cell 29: 1832-1847Abstract (164) Scholar,85.Kuppe C. al.Decoding myofibroblast origins fibrosis.Nature. 589: 281-286Crossref (225) Scholar,95.Shih Scholar,100.Winkler E.A. normal malformed vasculature.Science. 375: eabi7377Crossref (5) 101.Travaglini K.J. lung sequencing.Nature. 587: 619-625Crossref (470) 102.Kinchen J. al.Structural remodeling colonic inflammatory bowel disease.Cell. 175: 372-386Abstract (313) Validation selected situ used second selection.View Large Image ViewerDownload Hi-res image Download (PPT) text). selection. Many documented [10.Potente al.Basic aspects angiogenesis.Cell. 146: 873-887Abstract (1978) historical view proposes mainly late stages Scholar,10.Potente taking advantage retina paradigmatic experimental model angiogenesis, concept challenged [11.Park D.Y. al.Plastic blood-retinal barrier.Nat. 2017; 8: 15296Crossref (175) 12.Figueiredo A.M. al.Phosphoinositide 3-kinase-regulated maturation governs remodeling.Circulation. 142: 688-704Crossref (25) 13.Orlich M.M. al.Mural SRF controls migration, patterning flow.Circ. Res. 131: 308-327Crossref 14.Dieguez-Hurtado al.Loss factor RBPJ induces disease-promoting properties pericytes.Nat. 10: 2817Crossref 15.Teichert al.Pericyte-expressed Tie2 maturation.Nat. 16106Crossref (174) 16.Eilken H.M. al.Pericytes VEGF-induced sprouting through VEGFR1.Nat. 1574Crossref (134) showed that, yet achieved maturity seen formed permissive cell-cycle progression, morphological adaptation, migration [12.Figueiredo Scholar,13.Orlich setting, growth precedes expansion it still unclear why. One possibility expanding rapidly, ensure production sufficient signals, coherent inhibition activation blocks proliferation Scholar] nuclear translocation FOXO1 master regulator quiescence [17.Kobialka P. Graupera Revisiting PI3-kinase signalling angiogenesis.Vasc. 1: H125-H134Crossref examined absent, become angiogenic able proliferate [18.Mae M.A. blood–brain response loss.Circ. 128: e46-e62Crossref require expand. Nonetheless, fair acknowledge shown reduced coverage leads increased [19.Dave J.M. al.Pericyte ALK5/TIMP3 contributes morphogenesis developing brain.Dev. 47: 388-389Abstract (8) Although discrepancies highlight pericyte–EC interactions complex, they explained animal genetic interfere pericytes. Importantly, behaviors mostly tissues belonging CNS. Hence, given high abundance CNS, possible substantially outnumber them. interesting immature remain close contact entirety Scholar,20.Crouch E.E. al.Ensembles promote prenatal brain.Cell. 185: 3753-3769Abstract (11) suggests communication relies paracrine juxtracrine signaling, explain why Pu

Language: Английский

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Activation of aryl hydrocarbon receptor (AhR) in Alzheimer’s disease: role of tryptophan metabolites generated by gut host-microbiota

Journal of Molecular Medicine, Journal Year: 2023, Volume and Issue: 101(3), P. 201 - 222

Published: Feb. 9, 2023

Abstract Gut microbiota in interaction with intestinal host tissues influences many brain functions and microbial dysbiosis has been linked disorders, such as neuropsychiatric conditions Alzheimer’s disease (AD). l -tryptophan metabolites short-chained fatty acids (SCFA) are major messengers the microbiota-brain axis. Aryl hydrocarbon receptors (AhR) main targets of tryptophan microvessels which possess an enriched expression AhR protein. The Ah receptor is evolutionarily conserved, ligand-activated transcription factor not only a sensor xenobiotic toxins but also pleiotropic regulator both developmental processes age-related tissue degeneration. Major microbiota-produced involve indole derivatives, e.g., 3-pyruvic acid, 3-acetaldehyde, indoxyl sulfate, whereas indoleamine 2,3-dioxygenases (IDO/TDO) intestine cells activate kynurenine (KYN) pathway generating KYN metabolites, activators signaling. Chronic kidney (CKD) increases serum level sulfate promotes AD pathogenesis, it disrupts integrity blood–brain barrier (BBB) impairs cognitive functions. Activation signaling disturbs vascular homeostasis brain; (i) controls blood flow via renin-angiotensin system, (ii) inactivates endothelial nitric oxide synthase (eNOS), thus impairing NO production vasodilatation, (iii) induces oxidative stress, stimulates inflammation, cellular senescence, enhances calcification walls. All these alterations evident cerebral amyloid angiopathy (CAA) pathology. Moreover, can disturb circadian regulation probably affect glymphatic flow. It seems plausible that gut BBB activation aggravates Key messages Dysbiosis associated dementia disease. Tryptophan from host-microbiota to brain. aryl protein blood-brain barrier. inflammation pathology

Language: Английский

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Blood phosphorylated Tau181 reliably differentiates amyloid‐positive from amyloid‐negative subjects in the Alzheimer's disease continuum: A systematic review and meta‐analysis

Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 1, 2025

Abstract INTRODUCTION Blood‐based biomarkers seem promising for the diagnosis of Alzheimer's disease (AD). METHODS We performed a systematic review and meta‐analysis on potential blood phosphorylated Tau181 (p‐tau181) to differentiate amyloid‐positive (A+) amyloid‐negative (A−) subjects. Two meta‐analyses were conducted, showing mean p‐tau values in cerebrospinal fluid (CSF) A+ A− group, second comparing concentrations CSF among versus A‐ participants, by laboratory assessment method. RESULTS Eighteen studies (2764 5646 subjects) included. The single‐group showed higher p‐tau181 than group. In head‐to‐head meta‐analysis, reliably differentiated patients from participants. DISCUSSION Regardless technique, differentiates Therefore, it might have important applications early inclusion clinical trials AD patients. Highlights role blood‐based discriminating is still uncertain. Blood distinguishes allow trials.

Language: Английский

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Nutrition Strategies Promoting Healthy Aging: From Improvement of Cardiovascular and Brain Health to Prevention of Age-Associated Diseases

Nutrients, Journal Year: 2022, Volume and Issue: 15(1), P. 47 - 47

Published: Dec. 22, 2022

An increasing number of studies suggest that diet plays an important role in regulating aging processes and modulates the development most age-related diseases.The aim this review is to provide overview relationship between nutrition critical age-associated diseases.A literature was conducted survey recent pre-clinical clinical findings related nutritional factors modulation fundamental cellular molecular mechanisms their prevention genesis diseases aging.Studies show cardiovascular cerebrovascular diseases, neurodegenerative cognitive impairment dementia can be slowed down or prevented by certain diets with anti-aging action. The protective effects diets, at least part, may mediated beneficial macro- (protein, fat, carbohydrate) micronutrient (vitamins, minerals) composition.Certain such as Mediterranean diet, play a significant healthy preventing onset improving process itself. This latter strengthened incorporating fasting elements into diet. As dietary recommendations change age, should taken consideration well, when developing tailored needs elderly individuals. Future ongoing on complex interventions translating results preclinical investigations are expected lead novel guidelines for older adults near future.

Language: Английский

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Freshwater Cyanobacterial Toxins, Cyanopeptides and Neurodegenerative Diseases

Toxins, Journal Year: 2023, Volume and Issue: 15(3), P. 233 - 233

Published: March 21, 2023

Cyanobacteria produce a wide range of structurally diverse cyanotoxins and bioactive cyanopeptides in freshwater, marine, terrestrial ecosystems. The health significance these metabolites, which include genotoxic- neurotoxic agents, is confirmed by continued associations between the occurrence animal human acute toxic events and, long term, cyanobacteria neurodegenerative diseases. Major mechanisms related to neurotoxicity compounds (1) blocking key proteins channels; (2) inhibition essential enzymes mammalian cells such as protein phosphatases phosphoprotein well new molecular targets toll-like receptors 4 8. One widely discussed implicated includes misincorporation cyanobacterial non-proteogenic amino acids. Recent research provides evidence that non-proteinogenic acid BMAA produced have multiple effects on translation process bypasses proof-reading ability aminoacyl-tRNA-synthetase. Aberrant generated non-canonical may be factor neuronal death neurodegeneration. We hypothesize production acids more general mechanism, leading mistranslation, affecting homeostasis, targeting mitochondria eukaryotic cells. It can evolutionarily ancient initially developed control phytoplankton communities during algal blooms. Outcompeting gut symbiotic microorganisms lead dysbiosis, increased permeability, shift blood-brain-barrier functionality, eventually, mitochondrial dysfunction high-energy demanding neurons. A better understanding interaction metabolism nervous system will crucial target or prevent

Language: Английский

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siRNA drug delivery across the blood–brain barrier in Alzheimer's disease

Advanced Drug Delivery Reviews, Journal Year: 2023, Volume and Issue: 199, P. 114968 - 114968

Published: June 21, 2023

Language: Английский

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Young blood-mediated cerebromicrovascular rejuvenation through heterochronic parabiosis: enhancing blood-brain barrier integrity and capillarization in the aged mouse brain

GeroScience, Journal Year: 2024, Volume and Issue: 46(5), P. 4415 - 4442

Published: May 10, 2024

Language: Английский

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