Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

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

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

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Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Aug. 5, 2023

Microglia are the resident innate immune cells in brain with a major role orchestrating responses. They also provide frontline of host defense central nervous system (CNS) through their active phagocytic capability. Being professional phagocyte, microglia participate and autophagic clearance cellular waste debris as well toxic protein aggregates, which relies on optimal lysosomal acidification function. Defective microglial leads to impaired functions result perpetuation neuroinflammation progression neurodegeneration. Reacidification lysosomes has been shown reverse neurodegenerative pathology Alzheimer's disease. In this review, we summarize key factors mechanisms contributing impairment associated dysfunction microglia, how these defects contribute We further discuss techniques monitor pH therapeutic agents that can reacidify under disease conditions. Finally, propose future directions investigate lysosome-mitochondria crosstalk neuron-glia interaction for more comprehensive understanding its broader CNS physiological pathological implications.

Language: Английский

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Integrative multi-omics and systems bioinformatics in translational neuroscience: A data mining perspective

Journal of Pharmaceutical Analysis, Journal Year: 2023, Volume and Issue: 13(8), P. 836 - 850

Published: July 1, 2023

Bioinformatic analysis of large and complex omics datasets has become increasingly useful in modern day biology by providing a great depth information, with its application to neuroscience termed neuroinformatics. Data mining enabled the generation new hypotheses based on differentially regulated biological molecules associated disease mechanisms, which can be tested experimentally for improved diagnostic therapeutic targeting neurodegenerative diseases. Importantly, integrating multi-omics data using systems bioinformatics approach will advance understanding layered interactive network regulation that exchanges systemic knowledge facilitate development comprehensive human brain profile. In this review, we first summarize studies utilizing from individual type analysis, including epigenetics/epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, spatial omics, pertaining Alzheimer's disease, Parkinson's multiple sclerosis. We then discuss integration approaches, independent unsupervised methods, more intuitive informative interpretation obtained across different layers. further assess integrate provide convoluted insights offer proof-of-concept proposition towards reconstruction networks. Finally, recommend combination high dimensional experimental validation achieve translational applications biomarker discovery, development, elucidation mechanisms. conclude future perspectives opportunities applying integrative precision phenotyping diseases personalized medicine.

Language: Английский

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Blood–Brain Barrier-Targeting Nanoparticles: Biomaterial Properties and Biomedical Applications in Translational Neuroscience

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(5), P. 612 - 612

Published: May 10, 2024

Overcoming the blood–brain barrier (BBB) remains a significant hurdle in effective drug delivery to brain. While BBB serves as crucial protective barrier, it poses challenges delivering therapeutic agents their intended targets within brain parenchyma. To enhance for treatment of neurological diseases, several technologies circumvent have been developed last few years. Among them, nanoparticles (NPs) are one most versatile and promising tools. Here, we summarize characteristics NPs that facilitate penetration, including size, shape, chemical composition, surface charge, importantly, conjugation with various biological or synthetic molecules such glucose, transferrin, insulin, polyethylene glycol, peptides, aptamers. Additionally, discuss coating surfactants. A comprehensive overview common vitro vivo models NP penetration studies is also provided. The discussion extends discussing impairment under pathological conditions leveraging alterations delivery. Emphasizing need future uncover inherent properties NPs, review advocates role beyond systems calls efforts translating clinic therapeutics. Overall, stand out highly strategy precise targeting disorders.

Language: Английский

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The ion channels of endomembranes

Physiological Reviews, Journal Year: 2024, Volume and Issue: 104(3), P. 1335 - 1385

Published: March 7, 2024

The endomembrane system consists of organellar membranes in the biosynthetic pathway [endoplasmic reticulum (ER), Golgi apparatus, and secretory vesicles] as well those degradative (early endosomes, macropinosomes, phagosomes, autophagosomes, late lysosomes). These organelles/vesicles work together to synthesize, modify, package, transport, degrade proteins, carbohydrates, lipids, regulating balance between cellular anabolism catabolism. Large ion concentration gradients exist across endomembranes: Ca 2+ for most organelles H + acidic compartments. Ion (Na , K Cl − ) channels on control flux response cues, allowing rapid informational exchange cytosol organelle lumen. Recent advances proteomics, electrophysiology, luminal juxtaorganellar imaging have led molecular identification functional characterization about two dozen channels. For example, whereas IP3R1–3 mediate release from ER neurotransmitter hormone stimulation, TRPML1–3 TMEM175 lysosomal release, respectively, nutritional trafficking cues. This review aims summarize current understanding these channels, with a focus their subcellular localizations, permeation properties, gating mechanisms, cell biological functions, disease relevance.

Language: Английский

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Acidic Nanoparticles Restore Lysosomal Acidification and Rescue Metabolic Dysfunction in Pancreatic β-Cells under Lipotoxic Conditions

ACS Nano, Journal Year: 2024, Volume and Issue: 18(24), P. 15452 - 15467

Published: June 3, 2024

Type 2 diabetes (T2D), a prevalent metabolic disorder lacking effective treatments, is associated with lysosomal acidification dysfunction, as well autophagic and mitochondrial impairments. Here, we report series of biodegradable poly(butylene tetrafluorosuccinate-co-succinate) polyesters, comprising 1,4-butanediol linker varying ratios tetrafluorosuccinic acid (TFSA) succinic components, to engineer lysosome-acidifying nanoparticles (NPs). The synthesized NPs are spherical diameters ≈100 nm have low polydispersity good stability. Notably, TFSA NPs, which composed entirely TFSA, exhibit the strongest degradation capability superior acidifying properties. We further reveal significant downregulation vacuolar (H+)-ATPase subunits, responsible for maintaining acidification, in human T2D pancreatic islets, INS-1 β-cells under chronic lipotoxic conditions, tissues high-fat-diet (HFD) mice. Treatment restores function, activity, thereby improving function cells HFD mice lipid overload. Importantly, administration reduces insulin resistance improves glucose clearance. These findings highlight therapeutic potential T2D.

Language: Английский

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Comprehensive Overview of Alzheimer’s Disease: Etiological Insights and Degradation Strategies

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 6901 - 6901

Published: June 24, 2024

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and affects millions of individuals globally. AD associated with cognitive decline memory loss that worsens aging. A statistical report using U.S. data on estimates approximately 6.9 million suffer from AD, a number projected to surge 13.8 by 2060. Thus, there critical imperative pinpoint address its hallmark tau protein aggregation early prevent manage debilitating effects. Amyloid-β proteins are primarily formation plaques neurofibril tangles in brain. Current research efforts focus degrading amyloid-β or inhibiting their synthesis, particularly targeting APP processing hyperphosphorylation, aiming develop effective clinical interventions. However, navigating this intricate landscape requires ongoing studies trials treatments truly make difference. Genome-wide association (GWASs) across various cohorts identified 40 loci over 300 genes AD. Despite wealth genetic data, much remains be understood about functions these role process, prompting continued investigation. By delving deeper into associations, novel targets such as kinases, proteases, cytokines, degradation pathways, offer new directions for drug discovery therapeutic intervention This review delves biological pathways disrupted identifies how variations within could serve potential treatment strategies. Through comprehensive understanding molecular underpinnings researchers aim pave way more therapies can alleviate burden devastating disease.

Language: Английский

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Role of metabolic dysfunction and inflammation along the liver–brain axis in animal models with obesity-induced neurodegeneration

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(4), P. 1069 - 1076

Published: May 17, 2024

The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer’s disease Parkinson’s disease. Obesity-related conditions like type 2 diabetes non-alcoholic fatty liver exacerbate this relationship. Peripheral lipid accumulation, particularly in liver, initiates a cascade inflammatory processes that extend brain, influencing critical regulatory regions. Ceramide palmitate, key components, along with transporters lipocalin-2 apolipoprotein E, contribute neuroinflammation by disrupting blood–brain barrier integrity promoting gliosis. insulin resistance further exacerbates brain neuroinflammation. Preclinical interventions targeting peripheral metabolism signaling pathways have shown promise reducing animal models. However, translating these findings clinical practice requires investigation into human subjects. In conclusion, dysfunction, inflammation, are integral neurodegeneration. Understanding complex mechanisms holds potential for identifying novel therapeutic targets improving outcomes diseases.

Language: Английский

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A “turn-on” intracellular pH probe for the quantitative monitoring of lysosomal alkalization in living cells

Biosensors and Bioelectronics, Journal Year: 2025, Volume and Issue: 277, P. 117285 - 117285

Published: Feb. 19, 2025

Language: Английский

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Lysosomal acidification impairment in astrocyte-mediated neuroinflammation

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: March 10, 2025

Abstract Astrocytes are a major cell type in the central nervous system (CNS) that play key role regulating homeostatic functions, responding to injuries, and maintaining blood-brain barrier. also regulate neuronal functions survival by modulating myelination degradation of pathological toxic protein aggregates. have recently been proposed possess both autophagic activity active phagocytic capability which largely depend on sufficiently acidified lysosomes for complete cellular cargos. Defective lysosomal acidification astrocytes impairs their resulting accumulation debris, excessive myelin lipids, aggregates, ultimately contributes propagation neuroinflammation neurodegenerative pathology. Restoration impaired represent new neuroprotective strategy therapeutic direction. In this review, we summarize pathogenic factors, including neuroinflammatory signaling, metabolic stressors, lipid mediated toxicity, contribute impairment associated dysfunction astrocytes. We discuss astrocyte-mediated primarily context diseases along with other brain injuries. then highlight re-acidification as restore well degradative capacity conclude providing future perspectives phagocytes crosstalk CNS cells impart or effects.

Language: Английский

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