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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The role of inflammasomes in human diseases and their potential as therapeutic targets

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

Published: Jan. 5, 2024

Abstract Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response. Each inflammasome complex has three components: an upstream sensor molecule is connected to downstream effector such as caspase-1 through adapter ASC. Inflammasome formation typically occurs response infectious agents or cellular damage. The active then triggers activation, followed by secretion of pro-inflammatory cytokines pyroptotic cell death. Aberrant activation activity contribute development diabetes, cancer, several cardiovascular neurodegenerative disorders. As result, recent research increasingly focused on investigating mechanisms regulate assembly well potential targeting inflammasomes treat various diseases. Multiple clinical trials currently underway evaluate therapeutic distinct inflammasome-targeting therapies. Therefore, understanding how different disease pathology may have significant implications for developing novel strategies. In this article, we provide summary biological pathological roles health disease. We also highlight key evidence suggests could be strategy new disease-modifying therapies effective conditions.

Language: Английский

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A Comprehensive Review of Free Radicals, Oxidative Stress, and Antioxidants: Overview, Clinical Applications, Global Perspectives, Future Directions, and Mechanisms of Antioxidant Activity of Flavonoid Compounds

Journal of Chemistry, Journal Year: 2024, Volume and Issue: 2024, P. 1 - 21

Published: May 31, 2024

Absorption​ of free radicals in the body cannot be done by antioxidant compounds originating from human body, so exogenous antioxidants are required to help their natural action. Oxidative stress can caused an imbalance radical inhibitors and accumulation that enter cellular structures. Synthetic found external not primary choice because they harmful carcinogenic. Therefore, using ingredients provides a necessary alternative constructing novel antioxidants. Recent studies have highlighted critical analysis evaluation flavonoids unique class secondary metabolites plants used communities as traditional therapeutics with proven bioactivity. This could support new discoveries based on various herbal medicines addition, functional effectiveness against radicals. In this review, there several strengths discussion. First, study takes comprehensive approach covering aspects, including properties sources radicals, oxidative relation different diseases, defense mechanisms, specific mechanisms flavonoids. Second, focus antioxidants, especially flavonoids, also discussion about clinical applications studies, limitations, global perspectives, future research directions become references selection medicines. But, constraints should considered when interpreting findings review. mechanism is only discussed general one example compound (flavonoid) has potential antioxidant. lack regarding relationship between diseases Third, limited number investigated some discussed.

Language: Английский

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Dual-3DM³AD: Mixed Transformer Based Semantic Segmentation and Triplet Pre-Processing for Early Multi-Class Alzheimer’s Diagnosis

IEEE Transactions on Neural Systems and Rehabilitation Engineering, Journal Year: 2024, Volume and Issue: 32, P. 696 - 707

Published: Jan. 1, 2024

Alzheimer's Disease (AD) is a widespread, chronic, irreversible, and degenerative condition, its early detection during the prodromal stage of utmost importance. Typically, AD studies rely on single data modalities, such as MRI or PET, for making predictions. Nevertheless, combining metabolic structural can offer comprehensive perspective staging analysis. To address this goal, paper introduces an innovative multi-modal fusion-based approach named Dual-3DM ³ -AD. This model proposed accurate diagnosis by considering both PET image scans. Initially, we pre-process images in terms noise reduction, skull stripping 3D conversion using Quaternion Non-local Means Denoising Algorithm (QNLM), Morphology function Block Divider Model (BDM), respectively, which enhances quality. Furthermore, have adapted Mixed-transformer with Furthered U-Net performing semantic segmentation minimizing complexity. -AD consisted multi-scale feature extraction module extracting appropriate features from segmented images. The extracted are then aggregated Densely Connected Feature Aggregator Module (DCFAM) to utilize features. Finally, multi-head attention mechanism dimensionality softmax layer applied multi-class diagnosis. compared several baseline approaches help performance metrics. final results unveil that work achieves 98% accuracy, 97.8% sensitivity, 97.5% specificity, 98.2% f-measure, better ROC curves, outperforms other existing models multiclass

Language: Английский

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Targeting aging and age-related diseases with vaccines

Nature Aging, Journal Year: 2024, Volume and Issue: 4(4), P. 464 - 482

Published: April 15, 2024

Language: Английский

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Review on anti-alzheimer drug development: approaches, challenges and perspectives

RSC Advances, Journal Year: 2024, Volume and Issue: 14(16), P. 11057 - 11088

Published: Jan. 1, 2024

Alzheimer has many crucial factors that should be considered in order to get better results from clinical trials. Benzimidazole and its isosteres represent significant scaffolds for designing potential multi-target anti-alzheimer molecules.

Language: Английский

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Brain-targeted Tet-1 peptide-PLGA nanoparticles for berberine delivery against STZ-induced Alzheimer’s disease in a rat model: Alleviation of hippocampal synaptic dysfunction, Tau pathology, and amyloidogenesis

International Journal of Pharmaceutics, Journal Year: 2024, Volume and Issue: 658, P. 124218 - 124218

Published: May 9, 2024

Language: Английский

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Second-generation anti-amyloid monoclonal antibodies for Alzheimer’s disease: current landscape and future perspectives

Translational Neurodegeneration, Journal Year: 2025, Volume and Issue: 14(1)

Published: Jan. 27, 2025

Abstract Alzheimer’s disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from brains patients with AD, U.S. Food Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), donanemab (Kisunla™). Notably, received traditional approval after demonstrating clinical benefit, supporting cascade hypothesis. These MABs are categorized affinity to diverse conformational features Aβ, including monomer, fibril, protofibril, plaque forms well pyroglutamate Aβ. First-generation non-toxic monomeric solanezumab, bapineuzumab, crenezumab, failed demonstrate benefit trials. In contrast, second-generation aducanumab, lecanemab, donanemab, gantenerumab directed against species aggregates have shown that reducing deposition can be an effective strategy slow cognitive impairment AD. this review, we provide comprehensive overview current status, mechanisms, outcomes, limitations treatment Moreover, discuss perspectives future directions

Language: Английский

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The gut microbiota-immune-brain axis: Therapeutic implications

Cell Reports Medicine, Journal Year: 2025, Volume and Issue: unknown, P. 101982 - 101982

Published: March 1, 2025

Language: Английский

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Molecular Mechanisms of Alzheimer’s Disease Induced by Amyloid-β and Tau Phosphorylation Along with RhoA Activity: Perspective of RhoA/Rho-Associated Protein Kinase Inhibitors for Neuronal Therapy

Cells, Journal Year: 2025, Volume and Issue: 14(2), P. 89 - 89

Published: Jan. 10, 2025

Amyloid-β peptide (Aβ) is a critical cause of Alzheimer's disease (AD). It generated from amyloid precursor protein (APP) through cleavages by β-secretase and γ-secretase. γ-Secretase, which includes presenilin, regulated several stimuli. Tau has also been identified as significant factor in AD. In particular, phosphorylation crucial for neuronal impairment, phosphorylated detaches microtubules, leading to the formation neurofibrillary tangles destabilization microtubule structure. This instability microtubules damages axons dendrites, resulting impairment. Notably, Aβ linked phosphorylation. Another AD neuroinflammation, primarily occurring microglia. Microglia possess receptors that bind with Aβ, triggering expression release an inflammatory factor, although their main physiological function phagocytose debris pathogens brain. NF-κB activation plays major role neuroinflammation. Additionally, production reactive oxygen species (ROS) microglia contributes this microglia, superoxide produced NADPH oxidase, specifically NOX2. Rho GTPases play essential regulating various cellular processes, including cytoskeletal rearrangement, morphology changes, migration, transcription. The typical involves actin filament formation. Neurons, complex processes synapse connections, rely on dynamics structural support. Other brain cells, such astrocytes, oligodendrocytes, depend specific structures maintain unique architectures. Thus, aberrant regulation activity can disrupt filaments, altered cell morphology, changes synapses, potentially contributing diseases

Language: Английский

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