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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Explainable Artificial Intelligence in Alzheimer’s Disease Classification: A Systematic Review

Cognitive Computation, Journal Year: 2023, Volume and Issue: 16(1), P. 1 - 44

Published: Nov. 13, 2023

Abstract The unprecedented growth of computational capabilities in recent years has allowed Artificial Intelligence (AI) models to be developed for medical applications with remarkable results. However, a large number Computer Aided Diagnosis (CAD) methods powered by AI have limited acceptance and adoption the domain due typical blackbox nature these models. Therefore, facilitate among practitioners, models' predictions must explainable interpretable. emerging field (XAI) aims justify trustworthiness predictions. This work presents systematic review literature reporting Alzheimer's disease (AD) detection using XAI that were communicated during last decade. Research questions carefully formulated categorise into different conceptual approaches (e.g., Post-hoc, Ante-hoc, Model-Agnostic, Model-Specific, Global, Local etc.) frameworks (Local Interpretable Model-Agnostic Explanation or LIME, SHapley Additive exPlanations SHAP, Gradient-weighted Class Activation Mapping GradCAM, Layer-wise Relevance Propagation LRP, XAI. categorisation provides broad coverage interpretation spectrum from intrinsic Ante-hoc models) complex patterns Post-hoc taking local explanations global scope. Additionally, forms interpretations providing in-depth insight factors support clinical diagnosis AD are also discussed. Finally, limitations, needs open challenges research outlined possible prospects their usage detection.

Language: Английский

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Advances in Alzheimer's disease: A multifaceted review of potential therapies and diagnostic techniques for early detection

Neurochemistry International, Journal Year: 2024, Volume and Issue: 177, P. 105761 - 105761

Published: May 7, 2024

Language: Английский

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Dysfunctional Glucose Metabolism in Alzheimer’s Disease Onset and Potential Pharmacological Interventions

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(17), P. 9540 - 9540

Published: Aug. 23, 2022

Alzheimer’s disease (AD) is the most common age-related dementia. The alteration in metabolic characteristics determines prognosis. Patients at risk show reduced glucose uptake brain. Additionally, type 2 diabetes mellitus increases of AD with increasing age. Therefore, changes cerebral cortex may predict histopathological diagnosis AD. shifts and metabolism, insulin resistance, oxidative stress, abnormal autophagy advance pathogenesis syndrome. Here, we summarize role altered metabolism for discuss potential pharmacological interventions defects to encourage development novel therapeutic methods.

Language: Английский

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Non-Coding RNAs as Novel Regulators of Neuroinflammation in Alzheimer’s Disease

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: June 2, 2022

Alzheimer’s disease (AD) is one of the most common causes dementia. Although significant breakthroughs have been made in understanding progression and pathogenesis AD, it remains a worldwide problem public health burden. Thus, more efficient diagnostic therapeutic strategies are urgently required. The latest research studies revealed that neuroinflammation crucial AD. Non-coding RNAs (ncRNAs), including long noncoding (lncRNAs), microRNAs (miRNAs), circular (circRNAs), PIWI-interacting (piRNAs), transfer RNA-derived small (tsRNAs), strongly associated with AD-induced neuroinflammation. Furthermore, several ongoing pre-clinical currently investigating ncRNA as biomarkers interventions to provide new perspectives for AD diagnosis treatment. In this review, role different types ncRNAs during summarized order improve our etiology aid translation basic into clinical practice.

Language: Английский

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A novel Alzheimer’s disease prognostic signature: identification and analysis of glutamine metabolism genes in immunogenicity and immunotherapy efficacy

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: April 27, 2023

Abstract Alzheimer’s disease (AD) is characterized as a distinct onset and progression of cognitive functional decline associated with age, well specific neuropathology. It has been discovered that glutamine (Gln) metabolism plays crucial role in cancer. However, full investigation its still missing. This study intended to find confirm potential Gln-related genes AD using bioinformatics analysis. The discovery GlnMgs was made possible by the intersection WGCNA test 26 Gln-metabolism (GlnMgs). GlnMgs’ putative biological functions pathways were identified GSVA. LASSO method then used identify hub diagnostic efficiency four identifying AD. association between clinical characteristics also studied. Finally, GSE63060 utilized levels expression GlnMgs. Four (ATP5H, NDUFAB1, PFN2, SPHKAP). For function analysis, cell fate specification, atrioventricular canal development, neuron specification emphasized. ability differentiating exhibited good value. are linked They shed light on new biomarkers for tracking progression.

Language: Английский

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Anti-inflammatory role of gold nanoparticles in the prevention and treatment of Alzheimer's disease

Journal of Materials Chemistry B, Journal Year: 2023, Volume and Issue: 11(36), P. 8605 - 8621

Published: Jan. 1, 2023

Alzheimer's disease (AD) is a neurodegenerative that causes memory and cognitive dysfunction reduces person's decision-making reasoning functions. AD the leading cause of dementia in elderly. Patients with have increased expression pro-inflammatory cytokines nervous system, sustained inflammatory response impairs neuronal function. Meanwhile, long-term use anti-inflammatory drugs can reduce incidence to some extent. This confirms anti-neuroinflammation may be an effective treatment for AD. Gold nanoparticles (AuNPs) are emerging nanomaterial promising physicochemical properties, antioxidant. AuNPs neuroinflammation by inducing macrophage polarization toward M2 phenotype, reducing cytokine expression, blocking leukocyte adhesion, decreasing oxidative stress. Therefore, gradually attracting interest scholars used treating diseases drug delivery. Herein, we explored role mechanism The topic worth exploring future, not only help solve global public health problem but also provide reference other neuroinflammatory diseases.

Language: Английский

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New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(6), P. 5383 - 5383

Published: March 11, 2023

Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD a complex and multifactorial that responsible for 60–80% of dementia cases. Aging, genetic factors, epigenetic changes are the main risk factors AD. Two aggregation-prone proteins play decisive role in pathogenesis: β-amyloid (Aβ) hyperphosphorylated tau (pTau). Both them form deposits diffusible toxic aggregates brain. These biomarkers Different hypotheses have tried to explain pathogenesis served as platforms drug research. Experiments demonstrated both Aβ pTau might start processes necessary cognitive decline. The two pathologies act synergy. Inhibition formation has been old target. Recently, successful clearance by monoclonal antibodies raised new hopes treatments if detected at early stages. More recently, novel targets, e.g., improvements amyloid from brain, application small heat shock (Hsps), modulation chronic neuroinflammation different receptor ligands, microglial phagocytosis, increase myelination revealed

Language: Английский

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Therapeutic potential of glutaminyl cyclases: Current status and emerging trends

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(10), P. 103644 - 103644

Published: May 26, 2023

Glutaminyl cyclase (QC) activity has been identified as a key effector in distinct biological processes. Human glutaminyl-peptide cyclotransferase (QPCT) and cyclotransferase-like (QPCTL) are considered attractive therapeutic targets many human disorders, such neurodegenerative diseases, range of inflammatory conditions, well for cancer immunotherapy, because their capacity to modulate immune checkpoint proteins. In this review, we explore the functions structures QPCT/L enzymes highlight relevance. We also summarize recent developments discovery small-molecule inhibitors targeting these enzymes, including an overview preclinical clinical studies.

Language: Английский

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Hypometabolism, Alzheimer’s Disease, and Possible Therapeutic Targets: An Overview

Cells, Journal Year: 2023, Volume and Issue: 12(16), P. 2019 - 2019

Published: Aug. 8, 2023

The brain is a highly dynamic organ that requires constant energy source to function normally. This mostly supplied by glucose, simple sugar serves as the brain’s principal fuel source. Glucose transport across blood–brain barrier (BBB) primarily controlled via sodium-independent facilitated glucose transport, such transporter 1 (GLUT1) and 3 (GLUT3). However, other transporters, including GLUT4 sodium-dependent transporters SGLT1 SGLT6, have been reported in vitro vivo. When BBB endothelial layer crossed, neurons astrocytes can absorb using their GLUT1 GLUT3 transporters. then enters glycolytic pathway metabolized into adenosine triphosphate (ATP), which supplies support cellular functions. metabolism of are impacted several medical conditions, cause neurological neuropsychiatric symptoms. Alzheimer’s disease (AD), Parkinson’s (PD), epilepsy, traumatic injury (TBI), schizophrenia, etc., few most prevalent disorders, characterized decline or hypometabolism early course disease. Indeed, AD considered metabolic disorder related decreased metabolism, involving insulin resistance age-dependent mitochondrial dysfunction. Although conventional view reduced cerebral an effect neuronal loss consequent atrophy, growing body evidence points opposite, where prodromal at least precedes onset atrophy manifestation clinical underlying processes responsible for these abnormalities complicated remain poorly understood. review article provides comprehensive overview current understanding potential therapeutic targets.

Language: Английский

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