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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The interplay between cytokines, inflammation, and antioxidants: mechanistic insights and therapeutic potentials of various antioxidants and anti-cytokine compounds

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 178, С. 117177 - 117177

Опубликована: Июль 24, 2024

Cytokines regulate immune responses essential for maintaining homeostasis, as deregulated cytokine signaling can lead to detrimental outcomes, including inflammatory disorders. The antioxidants emerge promising therapeutic agents because they mitigate oxidative stress and modulate pathways. Antioxidants potentially ameliorate inflammation-related disorders by counteracting excessive cytokine-mediated responses. A comprehensive understanding of pathways the interplay with is paramount developing natural targeting helping improve clinical outcomes enhance quality life patients. Among these antioxidants, curcumin, vitamin C, D, propolis, allicin, cinnamaldehyde have garnered attention their anti-inflammatory properties potential benefits. This review highlights interrelationship between cytokines-mediated in various diseases approaches involving antioxidants.

Язык: Английский

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Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression

Frontiers in Synaptic Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Март 9, 2023

The synapse has consistently been considered a vulnerable and critical target within Alzheimer’s disease, loss is, to date, one of the main biological correlates cognitive decline disease. This occurs prior neuronal with ample evidence that synaptic dysfunction precedes this, in support idea failure is crucial stage disease pathogenesis. two pathological hallmarks abnormal aggregates amyloid or tau proteins, have had demonstrable effects on physiology animal cellular models There also growing these proteins may synergistic effect neurophysiological dysfunction. Here, we review some findings alterations what know from models. First, briefly summarize human suggest synapses are altered, including how this relates network activity. Subsequently, considered, highlighting mouse pathology role play dysfunction, either isolation examining pathologies interact specifically focuses function observed models, typically measured using electrophysiology calcium imaging. Following loss, it would be impossible imagine not alter oscillatory activity brain. Therefore, discusses underpin aberrant patterns seen patients. Finally, an overview key directions considerations field covered. includes current therapeutics targeted at but methods modulate rescue patterns. Other important future avenues note include non-neuronal cell types such as astrocytes microglia, mechanisms independent will certainly continue for foreseeable future.

Язык: Английский

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Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications

Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 15(1), С. 15 - 34

Опубликована: Окт. 16, 2024

Neuroprotection is a proactive approach to safeguarding the nervous system, including brain, spinal cord, and peripheral nerves, by preventing or limiting damage nerve cells other components. It primarily defends central system against injury from acute progressive neurodegenerative disorders. Oxidative stress, an imbalance between body's natural defense mechanisms generation of reactive oxygen species, crucial in developing neurological Due its high metabolic rate consumption, brain particularly vulnerable oxidative stress. Excessive ROS damages essential biomolecules, leading cellular malfunction neurodegeneration. Several disorders, Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple ischemic stroke, are associated with Understanding impact stress these conditions for new treatment methods. Researchers exploring using antioxidants molecules mitigate aiming prevent slow down progression diseases. By understanding intricate interplay scientists hope pave way innovative therapeutic preventive approaches, ultimately improving individuals' living standards.

Язык: Английский

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Misfolding and aggregation in neurodegenerative diseases: protein quality control machinery as potential therapeutic clearance pathways

Cell Communication and Signaling, Год журнала: 2024, Номер 22(1)

Опубликована: Авг. 30, 2024

The primary challenge in today's world of neuroscience is the search for new therapeutic possibilities neurodegenerative disease. Central to these disorders lies among other factors, aberrant folding, aggregation, and accumulation proteins, resulting formation toxic entities that contribute neuronal degeneration. This review concentrates on key proteins such as β-amyloid (Aβ), tau, α-synuclein, elucidating intricate molecular events underlying their misfolding aggregation. We critically evaluate mechanisms governing elimination misfolded shedding light potential strategies. specifically examine pathways endoplasmic reticulum (ER) unfolded protein response (UPR), chaperones, chaperone-mediated autophagy (CMA), intersecting signaling Keap1-Nrf2-ARE, along with connected through p62. Above all, we emphasize significance quality control mechanisms, encompassing interventions targeting regulation post-translational modifications, enhancement chaperones clearance. Additionally, focus current new, multi-target approaches. In conclusion, this systematically consolidates insights into emerging strategies predicated aggregates

Язык: Английский

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The duality of amyloid-β: its role in normal and Alzheimer’s disease states

Molecular Brain, Год журнала: 2024, Номер 17(1)

Опубликована: Июль 17, 2024

Abstract Alzheimer’s disease (AD) is a degenerative neurological condition that gradually impairs cognitive abilities, disrupts memory retention, and impedes daily functioning by impacting the cells of brain. A key characteristic AD accumulation amyloid-beta (Aβ) plaques, which play pivotal roles in progression. These plaques initiate cascade events including neuroinflammation, synaptic dysfunction, tau pathology, oxidative stress, impaired protein clearance, mitochondrial disrupted calcium homeostasis. Aβ also closely associated with other hallmark features AD, underscoring its significance. generated through cleavage amyloid precursor (APP) plays dual role depending on processing pathway. The non-amyloidogenic pathway reduces production has neuroprotective anti-inflammatory effects, whereas amyloidogenic leads to peptides, Aβ40 Aβ42, contribute neurodegeneration toxic effects AD. Understanding multifaceted Aβ, particularly crucial for developing effective therapeutic strategies target metabolism, aggregation, clearance aim mitigating detrimental consequences disease. This review aims explore mechanisms functions under normal abnormal conditions, examining both beneficial effects.

Язык: Английский

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Unraveling the therapeutic efficacy of resveratrol in Alzheimer’s disease: an umbrella review of systematic evidence

Nutrition & Metabolism, Год журнала: 2024, Номер 21(1)

Опубликована: Март 19, 2024

Abstract Context Resveratrol (RV), a natural compound found in grapes, berries, and peanuts, has been extensively studied for its potential treating Alzheimer’s disease (AD). RV shown promise inhibiting the formation of beta-amyloid plaques (Aβ) neurofibrillary tangles (NFTs), protecting against neuronal damage oxidative stress, reducing inflammation, promoting neuroprotection, improving function blood–brain barrier (BBB). However, conflicting results have reported, necessitating comprehensive umbrella review systematic reviews to provide an unbiased conclusion on therapeutic effectiveness AD. Objective The objective this study was systematically synthesize evaluate meta-analysis investigating role AD using data from both human animal studies. Data sources extraction Of 34 examining association between that were collected, six included based specific selection criteria. To identify pertinent studies, search conducted English-language peer-reviewed journals without any restrictions publication date until October 15, 2023. carried out across multiple databases, including Embase, MEDLINE (PubMed), Cochrane Library, Web Science, Google Scholar, utilizing appropriate terms relevant research field. AMSTAR-2 ROBIS tools also used quality risk bias reviews, respectively. Two researchers independently extracted analyzed data, resolving discrepancies through consensus. note, adhered PRIOR checklist. analysis This presented robust evidence supporting positive impacts AD, irrespective mechanisms involved. It indeed indicated all unanimously concluded consumption can be effective treatment Conclusion exhibits promising benefiting individuals with various mechanisms. observed enhance cognitive function, reduce Aβ accumulation, protect BBB, support mitochondrial facilitate synaptic plasticity, stabilize tau proteins, mitigate neuroinflammation commonly associated Graphical abstract

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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Alterations in the Processing of Platelet APP (Amyloid Beta Precursor Protein) in Alzheimer Disease: The Possible Nexus

Neuropsychopharmacology Reports, Год журнала: 2025, Номер 45(1)

Опубликована: Янв. 5, 2025

Alzheimer's disease (AD) is the most common neurodegenerative associated with development of dementia. The hallmarks AD neuropathology are accumulations amyloid peptide (Aβ) and neurofibrillary tangles (NFTs). Aβ derived from processing APP (amyloid beta precursor protein) by BACE1 (beta-secretase 1) γ-secretase through an amyloidogenic pathway. However, ADAM10/α-secretase (ADAM metallopeptidase domain 10) enzymes a non-amyloidogenic pathway produces soluble alpha (sAPPα), which has neuroprotective effect. It been shown that activated platelets implicated in pathogenesis AD, also increases platelet activation. Under physiological conditions, regulate synaptic plasticity increase neuronal differentiation regulation inflammatory response. overactivated contribute to AD. Activated represent main source circulating may be involved neuropathology. Therefore, there close relationship between platelets. This review discusses potential role how targeting reduce

Язык: Английский

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Protection of Alzheimer’s disease progression by a human-origin probiotics cocktail

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

Опубликована: Янв. 10, 2025

Microbiome abnormalities (dysbiosis) significantly contribute to the progression of Alzheimer's disease (AD). However, therapeutic efficacy microbiome modulators in protecting against these ailments remains poorly studied. Herein, we tested a cocktail unique probiotics, including 5 Lactobacillus and Enterococcus strains isolated from infant gut with proven modulating capabilities. We aimed determine probiotics cocktail's ameliorating AD pathology humanized mouse model APP/PS1 strains. Remarkably, feeding mice 1 × 1011 CFU per day drinking water for 16 weeks reduced cognitive decline (measured by Morris Water Maze test) markers, such as Aβ aggregation, microglia activation, neuroinflammation, preserved blood-brain barrier (BBB) tight junctions. The beneficial effects were linked inflammatory microbiome, leading decreased permeability inflammation both systemic circulation brain. Although male female showed overall improvements cognition biological females did not exhibit specific markers related permeability, suggesting that underlying mechanisms may differ depending on sex. In conclusion, our results suggest this could serve prophylactic agent reduce pathology. This is achieved beneficially improving intestinal junction proteins, reducing BBB, decreasing gut, blood circulation, brain, ultimately mitigating decline.

Язык: Английский

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