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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Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(11), С. 926 - 946

Опубликована: Авг. 6, 2024

Язык: Английский

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Glial Perturbation in Metal Neurotoxicity: Implications for Brain Disorders

Neuroglia, Год журнала: 2025, Номер 6(1), С. 4 - 4

Опубликована: Янв. 6, 2025

Overexposure of humans to heavy metals and essential poses a significant risk for the development neurological neurodevelopmental disorders. The mechanisms through which these exert their effects include generation reactive oxygen species, mitochondrial dysfunction, activation inflammatory pathways, disruption cellular signaling. function glial cells in brain maintenance homeostasis cannot be overlooked. are particularly susceptible metal-induced neurotoxicity. Accumulation promotes microglial activation, triggering responses that can coincide with other neurotoxicity, inducing alteration synaptic transmission, cognitive deficit, neuronal damage. In this review, we highlighted role dysfunction some selected neurodegenerative diseases We further dive into how exposure such as nickel, manganese, methyl mercury, cadmium, iron, arsenic, lead affect functions microglia, astrocytes, oligodendrocytes they on relation Potential therapeutic interventions use new improved chelating agents antioxidant therapies might approach alleviating perturbations.

Язык: Английский

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Amyloid-β and heart failure in Alzheimer’s disease: the new vistas

Frontiers in Medicine, Год журнала: 2025, Номер 12

Опубликована: Фев. 4, 2025

Alzheimer’s disease (AD) is the most common cause of dementia and represents 75% all types. AD neuropathology due to progressive deposition extracellular amyloid-beta (A β ) peptide intracellular hyperphosphorylated tau protein. The accumulated Aβ forms amyloid plaques, while protein neurofibrillary tangles (NFTs). Both plaques NFTs are hallmarks neuropathology. fundamental mechanism involved in pathogenesis still elusive, although more conceivable theory. Aβ-induced neurodegeneration associated neuroinflammation, oxidative stress, endoplasmic reticulum stress (ER), mitochondrial dysfunction contribute development cognitive impairment dementia. Of note, not only originated from brain but also produced peripherally and, via blood–brain barrier (BBB), can accumulate result AD. It has been shown that cardiometabolic conditions such as obesity, type 2 diabetes (T2D), heart failure (HF) regarded possible risk factors for other types dementia, vascular HF-induced chronic cerebral hypoperfusion, inflammation induce progression Interestingly, a systemic causes which turn affects peripheral organs, including heart. through deranged BBB be transported into circulation heart, leading HF. These findings suggest close relationship between However, exact AD-induced HF fully elucidated. Therefore, this review aims discuss link regarding potential role

Язык: Английский

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Early oxidative stress and DNA damage in Aβ-burdened hippocampal neurons in an Alzheimer’s-like transgenic rat model

Communications Biology, Год журнала: 2024, Номер 7(1)

Опубликована: Июль 14, 2024

Oxidative stress is a key contributor to AD pathology. However, the earliest role of pre-plaque neuronal oxidative stress, remains elusive. Using laser microdissected hippocampal neurons extracted from McGill-R-Thy1-APP transgenic rats we found that intraneuronal amyloid beta (iAβ)-burdened had increased expression genes related and DNA damage responses including Ercc2, Fancc, Sod2, Gsr, Idh1. was further evidenced by levels XPD (Ercc2) γH2AX foci, indicative double stranded breaks (DSBs), Ercc6, Rad51, Fen1, decreased Sirt6 in homogenates. We also synaptic plasticity (Grin2b (NR2B), CamkIIα, Bdnf, c-fos, Homer1A) protein TOP2β. Our findings indicate early accumulation iAβ, prior Aβ plaques, accompanied incipient DSBs may arise directly or maladaptive plasticity.

Язык: Английский

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Aβ42 and ROS dual-targeted multifunctional nanocomposite for combination therapy of Alzheimer’s disease

Journal of Nanobiotechnology, Год журнала: 2024, Номер 22(1)

Опубликована: Май 23, 2024

Abstract Amyloid-β (Aβ) readily misfolds into neurotoxic aggregates, generating high levels of reactive oxygen species (ROS), leading to progressive oxidative damage and ultimately cell death. Therefore, simultaneous inhibition Aβ aggregation scavenging ROS may be a promising therapeutic strategy alleviate Alzheimer’s disease pathology. Based on the previously developed antibody 1F12 that targets all forms 42 , we an dual-targeting nanocomposite using biodegradable mesoporous silica nanoparticles as carriers load ultra-small cerium oxide nanocrystals (bMSNs@Ce-1F12). By modifying brain-targeted rabies virus glycoprotein 29 (RVG29-bMSNs@Ce-1F12), this intelligent can efficiently target brain Aβ-rich regions. Combined with peripheral central nervous system treatments, RVG29-bMSNs@Ce-1F12 significantly AD symptoms by inhibiting misfolding, accelerating clearance, ROS. Furthermore, synergistic effect clearance exhibited dual-targeted also reduced burden hyperphosphorylated tau, alleviated glial activation, improved cognitive function in APP/PS1 mice. Our findings indicate is nanodrug facilitate multi-target treatment AD.

Язык: Английский

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Comprehensive Overview of Alzheimer’s Disease: Etiological Insights and Degradation Strategies

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(13), С. 6901 - 6901

Опубликована: Июнь 24, 2024

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and affects millions of individuals globally. AD associated with cognitive decline memory loss that worsens aging. A statistical report using U.S. data on estimates approximately 6.9 million suffer from AD, a number projected to surge 13.8 by 2060. Thus, there critical imperative pinpoint address its hallmark tau protein aggregation early prevent manage debilitating effects. Amyloid-β proteins are primarily formation plaques neurofibril tangles in brain. Current research efforts focus degrading amyloid-β or inhibiting their synthesis, particularly targeting APP processing hyperphosphorylation, aiming develop effective clinical interventions. However, navigating this intricate landscape requires ongoing studies trials treatments truly make difference. Genome-wide association (GWASs) across various cohorts identified 40 loci over 300 genes AD. Despite wealth genetic data, much remains be understood about functions these role process, prompting continued investigation. By delving deeper into associations, novel targets such as kinases, proteases, cytokines, degradation pathways, offer new directions for drug discovery therapeutic intervention This review delves biological pathways disrupted identifies how variations within could serve potential treatment strategies. Through comprehensive understanding molecular underpinnings researchers aim pave way more therapies can alleviate burden devastating disease.

Язык: Английский

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Using Redox Proteomics to Gain New Insights into Neurodegenerative Disease and Protein Modification

Antioxidants, Год журнала: 2024, Номер 13(1), С. 127 - 127

Опубликована: Янв. 20, 2024

Antioxidant defenses in biological systems ensure redox homeostasis, regulating baseline levels of reactive oxygen and nitrogen species (ROS RNS). Oxidative stress (OS), characterized by a lack antioxidant or an elevation ROS RNS, may cause modification biomolecules, being primarily absorbed proteins. As result both genome environment interactions, proteomics provides complete information about cell’s proteome, which changes continuously. Besides measuring protein expression levels, can also be used to identify modifications, localizations, the effects added agents, interactions between Several oxidative processes are frequently modify proteins post-translationally, including carbonylation, oxidation amino acid side chains, glycation, lipid peroxidation, produces highly alkenals. Reactive alkenals, such as 4-hydroxy-2-nonenal, cysteine (Cys), lysine (Lys), histidine (His) residues Michael addition, tyrosine (Tyr) nitrated Cys nitrosylated addition. nitrosative have been implicated many neurodegenerative diseases damage brain, especially vulnerable due large consumption dioxygen. Therefore, current methods applied for detection, identification, quantification great interest. This review describes main modifications classified chemical reactions. Finally, we discuss importance health describe analytical proteomics.

Язык: Английский

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Insulin resistance as the molecular link between diabetes and Alzheimer's disease

World Journal of Diabetes, Год журнала: 2024, Номер 15(7), С. 1430 - 1447

Опубликована: Июль 8, 2024

Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies indicated possible link between DM an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays vital protecting brain functions. Insulin resistance (IR), especially prevalent type 2 diabetes, is believed to play significant AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various functions, making individuals more susceptible defining features, such as the buildup beta-amyloid plaques tau protein tangles. Emerging research suggests addressing insulin-related issues might help reduce or even reverse changes linked This review aims explore rela-tionship AD, with focus on IR. It explores molecular mechanisms by which IR lead assesses current treatments target Understanding IR's connection AD offers new possibilities highlights importance continued this interdisciplinary field.

Язык: Английский

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Gelatin/PLA-loaded gold nanocomposites synthesis using Syzygium cumini fruit extract and their antioxidant, antibacterial, anti-inflammatory, antidiabetic and anti-Alzheimer’s activities

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 15, 2025

Nanotechnology has experienced significant advancements, attracting considerable attention in various biomedical applications. This innovative study synthesizes and characterizes Ge/PLA/AuNCs (gelatin/PLA/gold nanocomposites) using Syzygium cumini extract to evaluate their The UV–Visible spectroscopy results an absorption peak at 534 nm were primarily confirmed by synthesis. FTIR spectrum showed functional groups the XRD patterns crystalline shape structure of nanocomposites. FESEM HRTEM a oval with average particle size 21 nm. Ge/PLA/AuNC's remarkable antioxidant activity, as evidenced DPPH (70.84 ± 1.64%), ABTS activity (86.17 1.96%), reducing power (78.42 1.48%) concentration 100 μg/mL was observed. zone inhibition against Staphylococcus aureus (19.45 0.89 mm) Echericia coli (20.83 0.97 revealed excellent antibacterial Ge/PLA/AuNCs. anti-diabetic supported α-amylase (82.56 1.49%) α-glucosidase (80.27 1.57%). anti-Alzheimer AChE (76.37 1.18%) BChE (85.94 1.38%) enzymes. In vivo studies zebrafish embryos that have biocompatibility nontoxicity. SH-SY5Y cell line demonstrated improved viability (95.27 1.62%) enhanced neuronal growth following treatment. conclusion, present highlights cost-effective non-toxic properties Furthermore, it presents attractive promising approach for future

Язык: Английский

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