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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Mitochondrial Dynamics in Neurodegenerative Diseases: Unraveling the Role of Fusion and Fission Processes

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(17), С. 13033 - 13033

Опубликована: Авг. 22, 2023

Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration and death neurons, leading to range neurological symptoms. Despite heterogeneity these conditions, common denominator is implication mitochondrial dysfunction in their pathogenesis. Mitochondria play crucial role creating biomolecules, providing energy through adenosine triphosphate (ATP) generated oxidative phosphorylation (OXPHOS), producing reactive oxygen species (ROS). When they’re not functioning correctly, becoming fragmented losing membrane potential, they contribute diseases. In this review, we explore how mitochondria fuse undergo fission, especially context NDs. We discuss genetic protein mutations linked impact dynamics. also look at key regulatory proteins fusion (MFN1, MFN2, OPA1) fission (DRP1 FIS1), including post-translational modifications. Furthermore, highlight potential drugs that can influence By unpacking complex processes, aim direct research towards treatments improve life quality for people with challenging conditions.

Язык: Английский

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Innate immune activation in neurodegenerative diseases

Immunity, Год журнала: 2024, Номер 57(4), С. 790 - 814

Опубликована: Апрель 1, 2024

Язык: Английский

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Immune Activation in Alzheimer Disease

Annual Review of Immunology, Год журнала: 2024, Номер 42(1), С. 585 - 613

Опубликована: Март 1, 2024

Alzheimer disease (AD) is the most common neurodegenerative disease, and with no efficient curative treatment available, its medical, social, economic burdens are expected to dramatically increase. AD historically characterized by amyloid β (Aβ) plaques tau neurofibrillary tangles, but over last 25 years chronic immune activation has been identified as an important factor contributing pathogenesis. In this article, we review recent advances in our understanding of significance development AD. We describe how brain-resident macrophages, microglia, able detect Aβ species be activated, well consequences activated microglia discuss transcriptional changes AD, their unique heterogeneity humans, emerging strategies study human microglia. Finally, expose, beyond role peripheral signals different cell types activation.

Язык: Английский

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Microglia and amyloid plaque formation in Alzheimer's disease – Evidence, possible mechanisms, and future challenges

Journal of Neuroimmunology, Год журнала: 2024, Номер 390, С. 578342 - 578342

Опубликована: Апрель 5, 2024

Alzheimer's disease (AD) is a neurodegenerative characterized by cognitive decline that severely affects patients and their families. Genetic environmental risk factors, such as viral infections, synergize to accelerate the aging-associated neurodegeneration. factors for late-onset AD (LOAD), which accounts most cases, are predominantly implicated in microglial immune cell functions. As such, microglia play major role amyloid beta (Aβ) plaque (the pathological hallmark of AD) formation. This review aims provide an overview current knowledge regarding Aβ formation, well impact on morphological functional diversity plaques. Based this discussion, we seek identify challenges opportunities field with potential therapeutic implications.

Язык: Английский

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Neuroinflammation in Alzheimer disease

Nature reviews. Immunology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

Язык: Английский

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Comprehensive characterization of the transcriptional landscape in Alzheimer’s disease (AD) brains

Science Advances, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 3, 2025

Alzheimer’s disease (AD) is the leading dementia among elderly with complex origins. Despite extensive investigation into AD-associated protein-coding genes, involvement of noncoding RNAs (ncRNAs) and posttranscriptional modification (PTM) in AD pathogenesis remains unclear. Here, we comprehensively characterized landscape ncRNAs PTM events 1460 samples across six brain regions sourced from Mount Sinai/JJ Peters VA Medical Center Brain Bank Study Mayo cohorts, encompassing 33,321 long ncRNAs, 92,897 enhancer RNAs, 53,763 alternative polyadenylation events, 900,221 A-to-I RNA editing events. We additionally identified 25,351 aberrantly expressed altered associated traits further corresponding genes to construct regulatory networks. Furthermore, developed a user-friendly data portal, ADatlas, facilitating users exploring our results. Our study aims establish comprehensive platform for PTMs advance related research.

Язык: Английский

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Artificial intelligence for drug discovery and development in Alzheimer's disease

Current Opinion in Structural Biology, Год журнала: 2024, Номер 85, С. 102776 - 102776

Опубликована: Фев. 8, 2024

The complex molecular mechanism and pathophysiology of Alzheimer's disease (AD) limits the development effective therapeutics or prevention strategies. Artificial Intelligence (AI)-guided drug discovery combined with genetics/multi-omics (genomics, epigenomics, transcriptomics, proteomics, metabolomics) analysis contributes to understanding precision medicine disease, including AD AD-related dementia. In this review, we summarize AI-driven methodologies for AD-agnostic development, de novo design, virtual screening, prediction drug-target interactions, all which have shown potentials. particular, AI-based repurposing emerges as a compelling strategy identify new indications existing drugs AD. We provide several emerging targets from human genetics multi-omics findings highlight recent technologies their applications in using prototypical example. closing, discuss future challenges directions other neurodegenerative diseases.

Язык: Английский

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Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies

Journal of Neurology, Год журнала: 2024, Номер 271(6), С. 2992 - 3018

Опубликована: Март 30, 2024

Abstract Tauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation the microtubule-associated protein TAU, encoded gene MAPT . Neuronal dysfunction, dementia, neurodegeneration common features these often detrimental diseases. A neurodegenerative disease is considered primary tauopathy when mutations/haplotypes its cause TAU main feature. In case pathology observed but superimposed another hallmark, condition classified as secondary tauopathy. some tauopathies (e.g. -associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Alzheimer's (AD)) recognized significant pathogenic driver disease. many tauopathies, including Parkinson's (PD) Huntington's (HD), suggested to contribute development in others Niemann-Pick (NPC)) may only be bystander. The genetic mechanisms underlying not fully understood. this review, predispositions variants associated with both examined detail, assessing evidence for role conditions. We highlight less forms increase awareness disorders involvement their pathology. This approach contributes deeper understanding conditions also lay groundwork potential TAU-based therapeutic interventions various tauopathies.

Язык: Английский

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Brain responses to intermittent fasting and the healthy living diet in older adults

Cell Metabolism, Год журнала: 2024, Номер 36(8), С. 1668 - 1678.e5

Опубликована: Июнь 19, 2024

Язык: Английский

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