Neuronal cell death mechanisms in Alzheimer’s disease: An insight

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: Aug. 25, 2022

Regulated cell death (RCD) is an ordered and tightly orchestrated set of changes/signaling events in both gene expression protein activity responsible for normal development as well maintenance tissue homeostasis. Aberrant activation this pathway results by various mechanisms including apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-dependent death. Such pathological changes neurons alone or combination have been observed the pathogenesis neurodegenerative diseases Alzheimer’s disease (AD). Pathological hallmarks AD focus primarily on accumulation two main markers: amyloid β peptides abnormally phosphorylated tau proteins. These aggregates result formation A-β plaques neuro-fibrillary tangles (NFTs) induce neuroinflammation neurodegeneration over years to decades leading a multitude cognitive behavioral deficits. Autopsy findings reveal massive neuronal manifested form cortical volume shrinkage, reduction sizes gyri up 50% increase sulci. Multiple forms recorded from different studies conducted so far. However, understanding mechanism/s patients remains mystery trigger that aberrant RCD unknown because limited availability dying neurons. This review attempts elucidate process death, how it gets unregulated response intra extracellular stressors, their interplay role Disease human experimental models AD. Further we plan explore correlation amyloid-beta Tau with loss seen

Language: Английский

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Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(9), P. 1248 - 1263.e6

Published: Aug. 19, 2022

The drivers of sporadic Alzheimer's disease (AD) remain incompletely understood. Utilizing directly converted induced neurons (iNs) from AD-patient-derived fibroblasts, we identified a metabolic switch to aerobic glycolysis in AD iNs. Pathological isoform switching the glycolytic enzyme pyruvate kinase M (PKM) toward cancer-associated PKM2 conferred and transcriptional changes These alterations occurred via PKM2's lack activity nuclear translocation association with STAT3 HIF1α promote neuronal fate loss vulnerability. Chemical modulation prevented translocation, restored mature metabolism, reversed AD-specific gene expression changes, re-activated resilience against cell death.

Language: Английский

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Trem2 expression in microglia is required to maintain normal neuronal bioenergetics during development

Immunity, Journal Year: 2023, Volume and Issue: 57(1), P. 86 - 105.e9

Published: Dec. 29, 2023

Triggering receptor expressed on myeloid cells 2 (Trem2) is a cell-specific gene in brain microglia, with variants that are associated neurodegenerative diseases, including Alzheimer's disease. Trem2 essential for microglia-mediated synaptic refinement, but whether contributes to shaping neuronal development remains unclear. Here, we demonstrate plays key role controlling the bioenergetic profile of pyramidal neurons during development. In absence Trem2, developing hippocampal cornus ammonis (CA)1 not CA3 subfield displayed compromised energetic metabolism, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This was paralleled transcriptional rearrangement at birth, pervasive alteration metabolic, oxidative phosphorylation, signatures, delay maturation CA1 neurons. Our results unveil regulating metabolic fitness region-specific manner.

Language: Английский

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Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 197, P. 106520 - 106520

Published: May 3, 2024

Autism spectrum disorder (ASD) is a neurodevelopmental affecting 1 in 36 children and associated with physiological abnormalities, most notably mitochondrial dysfunction, at least subset of individuals. This systematic review meta-analysis discovered 204 relevant articles which evaluated biomarkers dysfunction ASD Significant elevations (all p < 0.01) the prevalence lactate (17%), pyruvate (41%), alanine (15%) creatine kinase (9%) were found ASD. Individuals had significant differences moderate to large effect sizes (Cohen's d' ≥ 0.6) compared controls mean pyruvate, lactate-to-pyruvate ratio, ATP, kinase. Some studies abnormal TCA cycle metabolites Thirteen controlled reported DNA (mtDNA) deletions or variations group blood, peripheral blood mononuclear cells, lymphocytes, leucocytes, granulocytes, brain. Meta-analyses (p copy number mtDNA overall ND1, ND4 CytB genes. Four linked specific haplogroups A series subgroup elevated respiration was increased sensitivity mitochondria stressors regression. Lactate, carnitine, acyl-carnitines clinical features such as delays language, social interaction, cognition, motor skills, repetitive behaviors gastrointestinal symptoms, although not all an association. acyl-carnitines, CoQ10, well variants, heteroplasmy, severity. Variability across biomarker primarily due collection processing techniques intrinsic heterogeneity population. Several alterations metabolism mothers neonates who develop Treatments targeting mitochondria, particularly carnitine ubiquinol, appear beneficial The link between common abnormalities individuals including disorders, oxidative stress, immune outlined. subtypes are discussed, one related regression, another microbiome metabolites, acyl-carnitines. Mechanisms linking function prenatal brain development postnatal Given multisystem complexity some ASD, this presents evidence for being central by contributing development, comorbidities diagnostic approach identify From evidence, it clear that many have may need be addressed order achieve optimal outcomes. fact during pregnancy early life eventually provides promise predictive Further improve understanding role better defining subgroups molecular mechanisms driving unique changes those

Language: Английский

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Mitochondrial metabolism in neural stem cells and implications for neurodevelopmental and neurodegenerative diseases

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: March 4, 2024

Abstract Mitochondria are cytoplasmic organelles having a fundamental role in the regulation of neural stem cell (NSC) fate during development and maintenance. During embryonic adult neurogenesis, NSCs undergo metabolic switch from glycolytic to oxidative phosphorylation with rise mitochondrial DNA (mtDNA) content, changes mitochondria shape size, physiological augmentation reactive oxygen species which together drive proliferate differentiate. Genetic epigenetic modifications proteins involved cellular differentiation (Mechanistic Target Rapamycin), proliferation (Wingless-type), hypoxia (Mitogen-activated protein kinase)–and all connected by common key regulatory factor Hypoxia Inducible Factor-1A–are deemed be responsible for shift and, consequently, NSC pathological conditions. Both primary dysfunction due mutations nuclear or mtDNA secondary (OXPHOS) metabolism, dynamics, organelle interplay pathways can contribute neurodevelopmental progressive neurodegenerative disorders. This review analyses physiology pathology starting available vitro vivo models highlights current knowledge concerning this process.

Language: Английский

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Transcriptional consequences of trisomy 21 on neural induction

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Jan. 30, 2024

Introduction Down syndrome, caused by trisomy 21, is a complex developmental disorder associated with intellectual disability and reduced growth of multiple organs. Structural pathologies are present at birth, reflecting embryonic origins. A fundamental unanswered question how an extra copy human chromosome 21 contributes to organ-specific that characterize individuals and, relevant the hallmark in affects neural development. We tested hypothesis exerts effects on development as early induction. Methods Bulk RNA sequencing was performed isogenic euploid induced pluripotent stem cells (iPSCs) successive stages induction: embryoid bodies Day 6, neuroectoderm 10, differentiated 17. Results Gene expression analysis revealed over 1,300 differentially expressed genes along differentiation pathway compared controls. Less than 5% gene changes included upregulated encoded every timepoint. Genes involved specific factor signaling pathways (WNT Notch), metabolism (including oxidative stress), extracellular matrix were altered cells. Further uncovered heterochronic genes. Conclusion Trisomy impacts discrete earliest The results suggest metabolic dysfunction arises embryogenesis may affect function more broadly.

Language: Английский

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Neural cell state shifts and fate loss in ageing and age-related diseases

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(7), P. 434 - 443

Published: June 2, 2023

Language: Английский

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Novel therapeutic approaches to target neurodegeneration

British Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 180(13), P. 1651 - 1673

Published: March 25, 2023

Ageing is the main risk factor common to most primary neurodegenerative disorders. Indeed, age‐related brain alterations have been long considered predispose neurodegeneration. Although protein misfolding and accumulation of toxic aggregates as causative events in neurodegeneration, several other biological pathways affected by ageing also contribute pathogenesis. Here, we discuss evidence showing involvement mechanisms controlling neuronal structure, gene expression, autophagy, cell metabolism neuroinflammation onset progression Furthermore, review therapeutic strategies currently under development or future approaches designed normalize these pathways, which may then increase resilience cope with species. In addition therapies targeting insoluble specifically associated each disorder, novel pharmacological be part combined rescue function.

Language: Английский

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Neuro-Vulnerability in Energy Metabolism Regulation: A Comprehensive Narrative Review

Nutrients, Journal Year: 2023, Volume and Issue: 15(14), P. 3106 - 3106

Published: July 11, 2023

This comprehensive narrative review explores the concept of neuro-vulnerability in energy metabolism regulation and its implications for metabolic disorders. The highlights complex interactions among neural, hormonal, pathways involved metabolism. key topics discussed include role organs, hormones, neural circuits maintaining balance. investigates association between disorders, such as obesity, insulin resistance, eating considering genetic, epigenetic, environmental factors that influence subsequent dysregulation. Neuroendocrine food intake expenditure are examined, with a focus on impact appetite dysregulation altered expenditure. neuroinflammation health is discussed, emphasizing bidirectional relationship neuroinflammatory processes. also evaluates use neuroimaging techniques studying their potential applications clinical settings. Furthermore, well contribution to examined. Potential therapeutic interventions targeting neuro-vulnerability, including pharmacological treatments lifestyle modifications, reviewed. In conclusion, understanding crucial addressing provides valuable insights into underlying neurobiological mechanisms health. Targeting holds promise developing innovative strategies prevention treatment ultimately improving outcomes.

Language: Английский

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Role of Serotonylation and SERT Posttranslational Modifications in Alzheimer's Disease Pathogenesis

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2024

In the context of an aging global population and imperative for innovative healthcare solutions, concept longevity clinics emerges as a timely vital area exploration. Unlike traditional medical facilities, offer unique approach to preclinical prevention, focusing on "prevention prevention" through utilization clocks biomarkers from healthy individuals. This article presents comprehensive overview clinics, encompassing descriptions existing models, development proposed framework, insights into biomarkers, wearable devices, therapeutic interventions. Additionally, economic justifications investing in are examined, highlighting significant growth potential biotechnology market its alignment with goals achieving active longevity. Anchored by Analytical Center, framework underscores importance data-driven decision-making innovation promoting prolonged enhanced human life. At present, there is no universally accepted standard model clinics. absence highlights need additional research ongoing improvements this field. Through synthesis scientific practical considerations, aims stimulate further discussion field ultimately contributing advancement practices aimed at extending enhancing

Language: Английский

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