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

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 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.

Язык: Английский

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Alzheimer's disease: From immunotherapy to immunoprevention

Cell, Год журнала: 2023, Номер 186(20), С. 4260 - 4270

Опубликована: Сен. 1, 2023

Язык: Английский

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Compilation of reported protein changes in the brain in Alzheimer’s disease

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 25, 2023

Abstract Proteomic studies of human Alzheimer’s disease brain tissue have potential to identify protein changes that drive disease, and new drug targets. Here, we analyse 38 published proteomic studies, generating a map in across thirteen regions, three stages (preclinical mild cognitive impairment, advanced disease), proteins enriched amyloid plaques, neurofibrillary tangles, cerebral angiopathy. Our dataset is compiled into searchable database (NeuroPro). We found 848 were consistently altered 5 or more studies. Comparison early-stage revealed associated with synapse, vesicle, lysosomal pathways show change early but widespread mitochondrial expression are only seen disease. Protein similar for regions considered vulnerable resistant. This resource provides insight highlights interest further study.

Язык: Английский

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Axonal energy metabolism, and the effects in aging and neurodegenerative diseases

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Июль 20, 2023

Abstract Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of (NDAs), such as Alzheimer’s disease, Parkinson’s Huntington’s Amyotrophic lateral sclerosis. Glucose is the major brain fuel glucose hypometabolism has been observed regions vulnerable to NDAs. Many susceptible are topological central hub connectome, linked by densely interconnected long-range axons. Axons, key components have high metabolic needs support neurotransmission other essential activities. Long-range axons particularly injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy often an early sign neurodegeneration. Recent ascribe axonal maintenance failures local dysregulation. With this review, we aim stimulate research exploring metabolically oriented neuroprotection strategies enhance or normalize bioenergetics NDA models. Here start summarizing evidence from human patients animal models reveal correlation between connectomic disintegration aging/NDAs. To encourage mechanistic investigations on how dysregulation occurs during aging/NDAs, first review current literature distinct subdomains: axon initial segments, myelinated arbors harboring pre-synaptic boutons. In each subdomain, focus organization, activity-dependent regulation system, external glial support. Second, mechanisms regulating nicotinamide adenine dinucleotide (NAD + ) homeostasis, molecule for energy metabolism processes, including NAD biosynthetic, recycling, consuming pathways. Third, highlight innate vulnerability connectome discuss its perturbation As deficits developing into NDAs, especially asymptomatic phase, they likely exaggerated further impaired energetic cost neural network hyperactivity, pathology. Future interrogating causal relationship vulnerability, axonopathy, amyloid/tau pathology, cognitive decline will provide fundamental knowledge therapeutic interventions.

Язык: Английский

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Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer’s disease via MFG-E8

Cell Reports Medicine, Год журнала: 2023, Номер 4(9), С. 101175 - 101175

Опубликована: Авг. 30, 2023

Synapse loss correlates with cognitive decline in Alzheimer's disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence any glial involvement removal AD remains to be established. Here we observe astrocytes and brains contain greater amounts of synaptic protein compared non-disease controls, that proximity amyloid-β plaques the APOE4 risk gene exacerbate this effect. In culture, primary phagocytose patient-derived synapses more than controls. Inhibiting interactions MFG-E8 rescues elevated engulfment by without affecting control uptake. Thus, promotes increased ingestion cells at least part via an opsonophagocytic mechanism potential targeted therapeutic manipulation.

Язык: Английский

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Protein translation: biological processes and therapeutic strategies for human diseases

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Фев. 23, 2024

Abstract Protein translation is a tightly regulated cellular process that essential for gene expression and protein synthesis. The deregulation of this increasingly recognized as critical factor in the pathogenesis various human diseases. In review, we discuss how deregulated can lead to aberrant synthesis, altered functions, disease progression. We explore key mechanisms contributing translation, including functional alterations factors, tRNA, mRNA, ribosome function. Deregulated leads abnormal expression, disrupted signaling, perturbed functions- all which contribute pathogenesis. development profiling techniques along with mass spectrometry-based proteomics, mRNA sequencing single-cell approaches have opened new avenues detecting diseases related errors. Importantly, highlight recent advances therapies targeting translation-related disorders their potential applications neurodegenerative diseases, cancer, infectious cardiovascular Moreover, growing interest lies targeted aimed at restoring precise control over diseased cells discussed. conclusion, comprehensive review underscores role its therapeutic target. Advancements understanding molecular deregulation, coupled therapies, offer promising improving outcomes Additionally, it will unlock doors possibility precision medicine by offering personalized deeper underpinnings future.

Язык: Английский

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Passive immunotherapy for Alzheimer's disease

Ageing Research Reviews, Год журнала: 2024, Номер 94, С. 102192 - 102192

Опубликована: Янв. 14, 2024

Alzheimer's disease (AD) is the most common neurodegenerative characterized by cognitive impairment with few therapeutic options. Despite many failures in developing AD treatment during past 20 years, significant advances have been achieved passive immunotherapy of very recently. Here, we review characteristics, clinical trial data, and mechanisms action for monoclonal antibodies (mAbs) targeting key players pathogenesis, including amyloid-β (Aβ), tau neuroinflammation modulators. We emphasized efficacy lecanemab donanemab on cognition amyloid clearance patients phase III trials discussed factors that may contribute to side effects anti-Aβ mAbs. In addition, provided important information mAbs or inflammatory regulators trials, indicated against mid-region pathogenic potential AD. conclusion, pathogenesis offers a promising strategy effective treatment.

Язык: Английский

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Innovation at the Intersection: Emerging Translational Research in Neurology and Psychiatry

Cells, Год журнала: 2024, Номер 13(10), С. 790 - 790

Опубликована: Май 7, 2024

Translational research in neurological and psychiatric diseases is a rapidly advancing field that promises to redefine our approach these complex conditions [...]

Язык: Английский

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p-tau Ser356 is associated with Alzheimer’s disease pathology and is lowered in brain slice cultures using the NUAK inhibitor WZ4003

Acta Neuropathologica, Год журнала: 2024, Номер 147(1)

Опубликована: Янв. 4, 2024

Abstract Tau hyperphosphorylation and aggregation is a common feature of many dementia-causing neurodegenerative diseases. can be phosphorylated at up to 85 different sites, there increasing interest in whether tau phosphorylation specific epitopes, by kinases, plays an important role disease progression. The AMP-activated protein kinase (AMPK)-related enzyme NUAK1 has been identified as potential mediator pathology, whereby NUAK1-mediated Ser356 prevents the degradation proteasome, further exacerbating accumulation. This study provides detailed characterisation association p-tau with progression Alzheimer’s identifying Braak stage-dependent increase levels almost ubiquitous presence neurofibrillary tangles. We also demonstrate, using sub-diffraction-limit resolution array tomography imaging, that co-localises synapses AD postmortem brain tissue, evidence this form may play roles To assess impacts pharmacological NUAK inhibition ex vivo system retains multiple cell types brain-relevant neuronal architecture, we treated postnatal mouse organotypic slice cultures from wildtype or APP/PS1 littermates commercially available NUAK1/2 inhibitor WZ4003. Whilst were no genotype-specific effects, found WZ4003 results culture-phase-dependent loss total Ser356, which corresponds reduction synaptic proteins. By contrast, application live human lowering alongside increased tubulin protein. work identifies differential responses adult will consider future developing tau-targeting therapeutics for disease.

Язык: Английский

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Artificial intelligence-based diagnosis of Alzheimer's disease with brain MRI images

European Journal of Radiology, Год журнала: 2023, Номер 165, С. 110934 - 110934

Опубликована: Июнь 20, 2023

Язык: Английский

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