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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Luteolin alleviates cognitive impairment in Alzheimer’s disease mouse model via inhibiting endoplasmic reticulum stress-dependent neuroinflammation

Acta Pharmacologica Sinica, Journal Year: 2021, Volume and Issue: 43(4), P. 840 - 849

Published: July 15, 2021

Language: Английский

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Reimagining cholinergic therapy for Alzheimer’s disease

Brain, Journal Year: 2022, Volume and Issue: 145(7), P. 2250 - 2275

Published: March 12, 2022

Currently, enhancement of cholinergic neurotransmission via cholinesterase inhibitors represents the main available approach to treat cognitive and behavioural symptoms early as well late stages Alzheimer's disease. Restoring system has been a primary means improving cognition in disease, four six approved therapies are acetylcholinesterase inhibitors. Memantine is an N-methyl-d-aspartate antagonist with well-documented clinical effect on symptoms, which often added potentiate their aducanumab, targeting amyloid pathology, recently approved. The early, progressive selective degeneration together its close relation deficits supports use therapy for This review provides updated view basal forebrain system, relevance It deals three aspects that form basis cholinergic-oriented origin, mechanism action, effects, advantages limits therapeutic approach. includes new overview involvement muscarinic receptors disease recent development highly M1 receptor agonists disease-modifying potential. also addresses discovery novel nerve growth factor metabolic pathway responsible trophic maintenance deregulation discusses studies evidence long-term efficacy inhibitor suggesting these drugs. classical symptomatic based judiciously discussed maximal best application. proposes alternatives should be developed amplify supplement treatments slow down or arrest progression.

Language: Английский

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Oxidative stress, the blood–brain barrier and neurodegenerative diseases: The critical beneficial role of dietary antioxidants

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 13(10), P. 3988 - 4024

Published: July 16, 2023

In recent years, growing awareness of the role oxidative stress in brain health has prompted antioxidants, especially dietary to receive attention as possible treatments strategies for patients with neurodegenerative diseases (NDs). The most widely studied antioxidants include active substances such vitamins, carotenoids, flavonoids and polyphenols. Dietary are found usually consumed foods fresh fruits, vegetables, nuts oils gaining popularity due recently their potential preventive protective agents against NDs, well abundant natural sources, generally non-toxic nature, ease long-term consumption. This review article examines development explores ‘two-sidedness’ blood–brain barrier (BBB) a nervous system an impeding use drug medicinal products and/or supplements prevention therapy reviews BBB permeability common suplements efficacy treatment NDs. Finally, current challenges future directions NDs using discussed, useful information on is provided.

Language: Английский

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Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Cells, Journal Year: 2024, Volume and Issue: 13(6), P. 511 - 511

Published: March 14, 2024

Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s (PD), traumatic brain injury (TBI) Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions these pathogeneses is currently not clearly understood. These show dysregulated inflammatory responses, activation neurons, glial cells, neurovascular unit damage associated with excessive release proinflammatory cytokines, chemokines, neurotoxic mediators, infiltration peripheral immune cells into brain, as well entry mediators through damaged endothelial blood–brain barrier tight junction proteins. Activation leads to many molecules that cause neuroinflammation neurodegeneration. Gulf War Illness (GWI) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) also dysfunctions. Currently, there no effective disease-modifying therapeutic options available for diseases. Human induced pluripotent stem cell (iPSC)-derived astrocytes, microglia, pericytes used models drug discovery. This review highlights certain recent trends in neuroinflammatory responses iPSC-derived applications

Language: Английский

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Tau Oligomers Neurotoxicity

Life, Journal Year: 2021, Volume and Issue: 11(1), P. 28 - 28

Published: Jan. 6, 2021

Although the mechanisms of toxic activity tau are not fully recognized, it is supposed that toxicity related rather to insoluble aggregates but its intermediate forms. It seems neurofibrillar tangles (NFTs) themselves, despite being composed tau, probably neither necessary nor sufficient for tau-induced neuronal dysfunction and toxicity. Tau oligomers (TauOs) formed during early stages aggregation pathological forms play a key role in eliciting loss neurons behavioral impairments several neurodegenerative disorders called tauopathies. They can be found tauopathic diseases, most common which Alzheimer’s disease (AD). Evidence co-occurrence b-amyloid, α-synuclein, into their forms, i.e., oligomers, suggests these species interact influence each other’s The mechanism responsible oligomeric neurotoxicity subject intensive investigation. In this review, we summarize recent literature on damaging effect TauOs stability genome function nucleus, energy production mitochondrial function, cell signaling synaptic plasticity, microtubule assembly, cytoskeleton axonal transport, effectiveness protein degradation system.

Language: Английский

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Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer’s disease via inhibition of ACSL4-dependent ferroptosis

Acta Pharmacologica Sinica, Journal Year: 2021, Volume and Issue: 43(1), P. 39 - 49

Published: March 25, 2021

Language: Английский

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Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease

Cells, Journal Year: 2021, Volume and Issue: 10(4), P. 779 - 779

Published: April 1, 2021

Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is major cause of death disability among the older population. Despite decades scientific research, underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking with pathogenesis remain obscure. In present study, we provided mechanistic link between dysbiotic neuroinflammation associated progression. Using mouse model AD, discovered unfavorable correlated abnormally elevated expression NLRP3 lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, observe significantly altered compositions young old 5xFAD mice compared age-matched non-transgenic mice. Moreover, demonstrated compromised barrier function as evident from tight junction adherens proteins Concurrently, observed increased IL-1β production gut. Consistent our hypothesis, gut–microbial–inflammasome activation positively enhanced astrogliosis microglial along higher brains These data indicate components may be an important trigger for subsequent downstream inflammatory potentially cytotoxic mediators, gastrointestinal promote inflammasome-mediated Thus, modulation strategy treatment AD-related neurological disorders genetically susceptible hosts.

Language: Английский

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The Main Alkaloids in Uncaria rhynchophylla and Their Anti-Alzheimer’s Disease Mechanism Determined by a Network Pharmacology Approach

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(7), P. 3612 - 3612

Published: March 31, 2021

Alzheimer’s disease (AD) is a growing concern in modern society, and effective drugs for its treatment are lacking. Uncaria rhynchophylla (UR) main alkaloids have been studied to treat neurodegenerative diseases such as AD. This study aimed uncover the key components mechanism of anti-AD effect UR through network pharmacology approach. The analysis identified 10 from based on HPLC that corresponded 90 targets. A potential alkaloid target-AD target indicated corynoxine, corynantheine, isorhynchophylline, dihydrocorynatheine, isocorynoxeine likely become AD treatment. KEGG pathway enrichment revealed Alzheimers (hsa05010) was most significantly enriched against Further 28 out targets were correlated with Aβ tau pathology. These validated using Gene Expression Omnibus (GEO) dataset. Molecular docking studies carried verify binding corynoxine corynantheine core related In addition, cholinergic synapse (hsa04725) dopaminergic (hsa04728) pathways enriched. Our findings indicate directly exert an by acting multiple pathological processes

Language: Английский

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Resveratrol and neuroprotection: an insight into prospective therapeutic approaches against Alzheimer’s disease from bench to bedside

Molecular Neurobiology, Journal Year: 2022, Volume and Issue: 59(7), P. 4384 - 4404

Published: May 12, 2022

Language: Английский

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