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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Lipidome disruption in Alzheimer’s disease brain: detection, pathological mechanisms, and therapeutic implications

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 27, 2025

Alzheimer's disease (AD) is among the most devastating neurodegenerative disorders with limited treatment options. Emerging evidence points to involvement of lipid dysregulation in development AD. Nevertheless, precise lipidomic landscape and mechanistic roles lipids pathology remain poorly understood. This review aims highlight significance lipidomics lipid-targeting approaches diagnosis We summarized connection between human brain AD at both genetic species levels. briefly introduced technologies discussed potential challenges areas future advancements field for research. To elucidate central role converging multiple pathological aspects AD, we reviewed current knowledge on interplay major features, including amyloid beta, tau, neuroinflammation. Finally, assessed progresses obstacles lipid-based therapeutics proposed strategies leveraging

Language: Английский

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Imaging Amyloid‐β Membrane Interactions: Ion‐Channel Pores and Lipid‐Bilayer Permeability in Alzheimer's Disease

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(25)

Published: March 6, 2023

The accumulation of the amyloid-β peptides (Aβ) is central to development Alzheimer's disease. mechanism by which Aβ triggers a cascade events that leads dementia topic intense investigation. self-associates into series complex assemblies with different structural and biophysical properties. It interaction these oligomeric, protofibril fibrillar lipid membranes, or membrane receptors, results in permeability loss cellular homeostasis, key event disease pathology. can have an array impacts on reports included: carpeting effect; detergent ion-channel pore formation. Recent advances imaging interactions are providing clearer picture induced disruption. Understanding relationship between structures will inform therapeutics targeting cytotoxicity.

Language: Английский

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Cholesterol and Lipid Rafts in the Biogenesis of Amyloid-β Protein and Alzheimer's Disease

Annual Review of Biophysics, Journal Year: 2024, Volume and Issue: 53(1), P. 455 - 486

Published: Feb. 21, 2024

Cholesterol has been conjectured to be a modulator of the amyloid cascade, mechanism that produces amyloid-β (Aβ) peptides implicated in onset Alzheimer's disease. We propose cholesterol impacts genesis Aβ not through direct interaction with proteins bilayer, but indirectly by inducing liquid-ordered phase and accompanying liquid-liquid separations, which partition cascade different lipid domains ultimately endocytotic pathways. explore full process context phases induced cholesterol, including protein partitioning into domains, mechanisms endocytosis experienced secretases, pH-controlled activation precursor secretases specific environments. Outstanding questions on essential role are identified for future studies.

Language: Английский

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Possible Role of Fibrinaloid Microclots in Postural Orthostatic Tachycardia Syndrome (POTS): Focus on Long COVID

Journal of Personalized Medicine, Journal Year: 2024, Volume and Issue: 14(2), P. 170 - 170

Published: Jan. 31, 2024

Postural orthostatic tachycardia syndrome (POTS) is a common accompaniment of variety chronic, inflammatory diseases, including long COVID, as are small, insoluble, 'fibrinaloid' microclots. We here develop the argument, with accompanying evidence, that fibrinaloid microclots, through their ability to block flow blood microcapillaries and thus cause tissue hypoxia, not simply correlated but in fact, by preceding it, may be chief intermediary POTS, which body's exaggerated 'physiological' response hypoxia. Similar reasoning accounts for symptoms bundled under term 'fatigue'. Amyloids known membrane disruptors, when targets nerve membranes, this can explain neurotoxicity hence autonomic nervous system dysfunction contributes POTS. Taken together view, we indicate microclots serve link POTS fatigue COVID manner at once both mechanistic explanatory. This has clear implications treatment such diseases.

Language: Английский

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Mechanosensitive Piezo1 channel in physiology and pathophysiology of the central nervous system

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 90, P. 102026 - 102026

Published: July 31, 2023

Since the discovery of mechanosensitive Piezo1 channel in 2010, there has been a significant amount research conducted to explore its regulatory role physiology and pathology various organ systems. Recently, growing body compelling evidence emerged linking activity health disease central nervous system. However, exact mechanisms underlying these associations remain inadequately comprehended. This review systematically summarizes current on implications for system mechanobiology, retrospects results demonstrating cell types within system, including neural stem cells, neurons, oligodendrocytes, microglia, astrocytes, brain endothelial cells. Furthermore, discusses understanding involvement disorders, such as Alzheimer's disease, multiple sclerosis, glaucoma, stroke, glioma.

Language: Английский

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The structure of tyrosine-10 favors ionic conductance of Alzheimer’s disease-associated full-length amyloid-β channels

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 13, 2024

Abstract Amyloid β (Aβ) ion channels destabilize cellular ionic homeostasis, which contributes to neurotoxicity in Alzheimer’s disease. The relative roles of various Aβ isoforms are poorly understood. We use bilayer electrophysiology, AFM imaging, circular dichroism, FTIR and fluorescence spectroscopy characterize channel activities four most prevalent peptides, 1-42 , 1-40 their pyroglutamylated forms (AβpE 3-42 AβpE 3-40 ) correlate them with the peptides’ structural features. Solvent-induced splitting tyrosine-10 is discovered used assess sequestration from solvent membrane insertion. effectively embeds lipid membranes, contains large fraction β-sheet a β-barrel-like structure, multi-subunit pores displays well-defined In contrast, other peptides partially solvent-exposed, contain minimal form less-ordered assemblies, produce irregular currents. These findings illuminate basis through permeabilization may help develop therapies that target Aβ-membrane interactions.

Language: Английский

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Exploring pathological link between antimicrobial and amyloid peptides

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(17), P. 8713 - 8763

Published: Jan. 1, 2024

Amyloid peptides (AMYs) and antimicrobial (AMPs) are considered as the two distinct families of peptides, characterized by their unique sequences, structures, biological functions, specific pathological targets. However, accumulating evidence has revealed intriguing connections between these peptide in context microbial infection neurodegenerative diseases. Some AMYs AMPs share certain structural functional characteristics, including ability to self-assemble, presence β-sheet-rich membrane-disrupting mechanisms. These shared features enable possess activity acquire amyloidogenic properties. Despite limited studies on AMYs-AMPs systems, cross-seeding phenomenon emerged a crucial factor bidirectional communication pathogenesis diseases host defense against infections. In this review, we examine recent developments potential interplay AMPs, well implications for both infectious By discussing current progress challenges emerging field, account aims inspire further research investments enhance our understanding intricate molecular crosstalk AMPs. This knowledge holds great promise development innovative therapies combat infections disorders.

Language: Английский

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Lateral nanoarchitectonics from nano to life: Ongoing challenge in interfacial chemical science

Chemical Science, Journal Year: 2024, Volume and Issue: 15(45), P. 18715 - 18750

Published: Jan. 1, 2024

The construction of functional structures within a single plane still has lot challenges. This review article will help us find new groundbreaking directions in lateral nanoarchitectonics toward advanced material organization.

Language: Английский

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Spike Protein Fragments Promote Alzheimer’s Amyloidogenesis

ACS Applied Materials & Interfaces, Journal Year: 2023, Volume and Issue: 15(34), P. 40317 - 40329

Published: Aug. 16, 2023

Alzheimer's disease (AD) is a major cause of dementia inducing memory loss, cognitive decline, and mortality among the aging population. While amyloid aggregation peptide Aβ has long been implicated in neurodegeneration AD, primarily through production toxic polymorphic aggregates reactive oxygen species, viral infection less explicit role etiology brain disease. On other hand, while COVID-19 pandemic known to harm human organs function, its adverse effects on AD pathobiology conditions remain unclear. Here we first identified amyloidogenic potential

Language: Английский

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