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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Glucagon-like peptide-1 receptor: mechanisms and advances in therapy

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

Опубликована: Сен. 18, 2024

The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and found primarily on surfaces various cell types within human body. This specifically interacts with GLP-1, key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, several other crucial biological functions. In recent years, GLP-1 medications have become focal point medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, broad development prospects. article thoroughly traces developmental milestones drugs, from initial discovery clinical application, detailing evolution diverse along distinct pharmacological properties. Additionally, this paper explores potential applications agonists (GLP-1RAs) fields such neuroprotection, anti-infection measures, reduction inflammation, enhancement cardiovascular function. It provides in-depth assessment effectiveness GLP-1RAs across multiple body systems-including nervous, cardiovascular, musculoskeletal, digestive systems. includes integrating latest trial data delving into signaling pathways mechanisms. primary goal emphasize extensive benefits using treating spectrum diseases, obesity, non-alcoholic fatty liver disease (NAFLD), neurodegenerative musculoskeletal forms cancer. ongoing new indications for drugs offers promising prospects further expanding interventions, showcasing field.

Язык: Английский

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Alzheimer’s disease and its treatment–yesterday, today, and tomorrow

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Май 24, 2024

Alois Alzheimer described the first patient with Alzheimer’s disease (AD) in 1907 and today AD is most frequently diagnosed of dementias. a multi-factorial neurodegenerative disorder familial, life style comorbidity influences impacting global population more than 47 million projected escalation by 2050 to exceed 130 million. In USA demographic encompasses approximately six individuals, expected increase surpass 13 2050, antecedent phase AD, recognized as mild cognitive impairment (MCI), involves nearly 12 individuals. The economic outlay for management AD-related decline estimated at 355 billion USD. addition, intensifying prevalence cases countries modest intermediate income further enhances urgency therapeutically cost-effective treatments improving quality patients their families. This narrative review evaluates pathophysiological basis an initial focus on therapeutic efficacy limitations existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, N-methyl-D-aspartate receptor (NMDA) allosteric modulator, memantine. hypothesis amyloid-β (Aβ) tau are appropriate targets have potential halt progress critically analyzed particular clinical trial data anti-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab donanemab. challenges dogma targeting Aβ will benefit majority subjects MABs unlikely be “magic bullet”. A comparison benefits disadvantages different classes forms determining new directions research alternative drug undergoing pre-clinical assessments. we discuss stress importance treatment co-morbidities, including hypertension, diabetes, obesity depression known risk developing AD.

Язык: Английский

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Targeting dysregulated lipid metabolism for the treatment of Alzheimer's disease and Parkinson's disease: Current advancements and future prospects

Neurobiology of Disease, Год журнала: 2024, Номер 196, С. 106505 - 106505

Опубликована: Апрель 19, 2024

Alzheimer's and Parkinson's diseases are two of the most frequent neurological diseases. The clinical features AD memory decline cognitive dysfunction, while PD mainly manifests as motor dysfunction such limb tremors, muscle rigidity abnormalities, slow gait. Abnormalities in cholesterol, sphingolipid, glycerophospholipid metabolism have been demonstrated to directly exacerbate progression by stimulating Aβ deposition tau protein tangles. Indirectly, abnormal lipids can increase burden on brain vasculature, induce insulin resistance, affect structure neuronal cell membranes. Abnormal lipid leads through inducing accumulation α-syn, mitochondria endoplasmic reticulum, ferroptosis. Great progress has made targeting abnormalities for treatment recent years, like metformin, insulin, peroxisome proliferator-activated receptors (PPARs) agonists, monoclonal antibodies apolipoprotein E (ApoE). This review comprehensively summarizes involvement dysregulated pathogenesis PD, application Lipid Monitoring, emerging regulatory drug targets. A better understanding lipidological bases may pave way developing effective prevention methods neurodegenerative disorders.

Язык: Английский

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Type 2 Diabetes Mellitus Exacerbates Pathological Processes of Parkinson's Disease: Insights from Signaling Pathways Mediated by Insulin Receptors

Neuroscience Bulletin, Год журнала: 2025, Номер unknown

Опубликована: Янв. 4, 2025

Язык: Английский

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A Comprehensive Approach to Parkinson’s Disease: Addressing Its Molecular, Clinical, and Therapeutic Aspects

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(13), С. 7183 - 7183

Опубликована: Июнь 29, 2024

Parkinson's disease (PD) is a gradually worsening neurodegenerative disorder affecting the nervous system, marked by slow progression and varied symptoms. It second most common disease, over six million people in world. Its multifactorial etiology includes environmental, genomic, epigenetic factors. Clinical symptoms consist of non-motor motor symptoms, with being classic presentation. Therapeutic approaches encompass pharmacological, non-pharmacological, surgical interventions. Traditional pharmacological treatment consists administering drugs (MAOIs, DA, levodopa), while emerging evidence explores potential antidiabetic agents for neuroprotection gene therapy attenuating parkinsonian Non-pharmacological treatments, such as exercise, calcium-rich diet, adequate vitamin D supplementation, aim to prevent complications. For those patients who have medically induced side effects and/or refractory surgery therapeutic option. Deep brain stimulation primary option, associated symptom improvement. Levodopa/carbidopa intestinal gel infusion through percutaneous endoscopic gastrojejunostomy portable pump succeeded reducing "off" time, where occur, increasing "on" time. This article aims address general aspects PD provide comparative comprehensive review conventional latest advancements treatments PD. Nevertheless, further studies are required optimize suitable alternatives.

Язык: Английский

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Molecular mechanisms of semaglutide and liraglutide as a therapeutic option for obesity

Frontiers in Nutrition, Год журнала: 2024, Номер 11

Опубликована: Апрель 29, 2024

Obesity, a chronic global health problem, is associated with an increase in various comorbidities, such as cardiovascular disease, type 2 diabetes mellitus, hypertension, and certain types of cancer. The increasing prevalence obesity requires research into new therapeutic strategies. Glucagon-like peptide-1 receptor agonists, specifically semaglutide liraglutide, designed for mellitus treatment, have been explored drugs the treatment obesity. This minireview describes molecular mechanisms liraglutide different metabolic pathways, its mechanism action processes appetite regulation, insulin secretion, glucose homeostasis, energy expenditure, lipid metabolism. Finally, several clinical trial outcomes are described to show safety efficacy these management.

Язык: Английский

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Sex-specific signatures of GLP-1 and amylin on resting state brain activity and functional connectivity in awake rats.

Neuropharmacology, Год журнала: 2025, Номер unknown, С. 110348 - 110348

Опубликована: Фев. 1, 2025

Gut-produced glucagon-like peptide-1 (GLP-1) and pancreas-made amylin robustly reduce food intake by directly or indirectly affecting brain activity. While for both peptides a direct action in the hindbrain hypothalamus is likely, few studies examined their impact on whole activity rodents did so evaluating male under anesthesia. However, sex anesthesia may significantly alter influence of feeding controlling molecules Therefore, we investigated effect GLP-1 functional connectivity (FC) awake adult female rats using resting-state magnetic resonance imaging (rsfMRI). We further relationship between altered subsequent response to GLP-1. observed divergent effects FC patterns. Most importantly correlation analysis behavior revealed that different areas potentially drive reduced rats. Our findings underscore distributed distinctly neural network engaged each these anorexic suggest be primary drivers outcome Moreover, prominent alterations not typically associated with sexes either indicate novel centers alternatively involvement substances behaviors beyond metabolism. The latter question potential translational significance as analogues are clinically utilized.

Язык: Английский

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Examining multimorbidity contributors to dementia over time

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(2)

Опубликована: Фев. 1, 2025

Abstract INTRODUCTION Multimorbidity is associated with increased risk of dementia, but previous estimation the joint contribution constituent conditions to dementia incidence did not model additive contributions or temporal proximity in sequential onset conditions. METHODS Data were analyzed from 9944 Health and Retirement Study participants Medicare fee‐for‐service beneficiaries, ages 68–99, without Alzheimer's disease related dementias (ADRD) at baseline, 1998–2016. ADRD chronic condition encoded using validated claims algorithms. We estimated absolute eight longitudinal extension average attributable fraction (LE‐AAF). RESULTS Hypertension, acute myocardial infarction, atrial fibrillation, diabetes, heart failure, ischemic disease, stroke, arthritis additively accounted for 71.8% (95% confidence interval [CI]: 62.9%–79.1%) incident cases based on LE‐AAF. DISCUSSION Our findings suggest that multimorbidity plays a pivotal role incidence. Targeting constituents cardiovascular path may contribute most lowering risk. Highlights Most (71.8%) Hypertension was largest contributor Confidence intervals smallest dementia. Longitudinal fractions (LE‐AAFs) explicitly consider patterns comorbidities. Acute infarction significantly

Язык: Английский

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Some Novel Therapies in Parkinson’s Disease: A Promising Path Forward or Not Yet? A Systematic Review of the Literature

Biomedicines, Год журнала: 2024, Номер 12(3), С. 549 - 549

Опубликована: Фев. 29, 2024

In light of the unsuccessful traditional therapies for Parkinson's disease (PD) overmany years, there is an unmet need development novel to alleviate symptoms PD retardation or halt progression itself. This systematic review aims critically update some most promising treatments including gene therapy, cell-based therapies, targeted drug delivery, and neuroprotective agents, focusing on their challenges, limitations future directions in research. Gene therapy encouraging, with AAV-based approaches targeting neurotrophic factors, dopamine production, neuronal circuits animal clinical trials. A approach delivery involves use nanotechnology create vehicles that can traverse blood-brain barrier deliver medications specifically regions brain affected by PD. Neuroprotective agents are compounds have ability protect neurons from degeneration death, they hold great promise evolution disease-modifying Magnetic field a non-invasive method promotes neural plasticity The establishment standardized protocols human studies, safety, ethical considerations, cost-effectiveness major challenges research therapies. represents path toward effective personalized

Язык: Английский

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