ApoE Cascade Hypothesis in the pathogenesis of Alzheimer’s disease and related dementias

Neuron, Год журнала: 2022, Номер 110(8), С. 1304 - 1317

Опубликована: Март 16, 2022

Язык: Английский

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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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Pesticides impacts on human health and the environment with their mechanisms of action and possible countermeasures

Heliyon, Год журнала: 2024, Номер 10(7), С. e29128 - e29128

Опубликована: Апрель 1, 2024

Pesticides are chemical constituents used to prevent or control pests, including insects, rodents, fungi, weeds, and other unwanted organisms. Despite their advantages in crop production disease management, the use of pesticides poses significant hazards environment public health. Pesticide elements have now perpetually entered our atmosphere subsequently contaminated water, food, soil, leading health threats ranging from acute chronic toxicities. can cause toxicity if a high dose is inhaled, ingested, comes into contact with skin eyes, while prolonged recurrent exposure leads toxicity. produce different types toxicity, for instance, neurotoxicity, mutagenicity, carcinogenicity, teratogenicity, endocrine disruption. The pesticide formulation may depend on specific active ingredient presence synergistic inert compounds that enhance modify its Safety concerns need hour contemporary pesticide-induced hazards. effectiveness implementation current legislature providing ample protection human key concerns. This review explored comprehensive summary regarding updated impacts advanced safety legislation. Implementing regulations, proper training, education help mitigate negative promote safer more sustainable agricultural practices.

Язык: Английский

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The amyloid cascade hypothesis: an updated critical review

Brain, Год журнала: 2023, Номер 146(10), С. 3969 - 3990

Опубликована: Май 15, 2023

Results from recent clinical trials of antibodies that target amyloid-β (Aβ) for Alzheimer's disease have created excitement and been heralded as corroboration the amyloid cascade hypothesis. However, while Aβ may contribute to disease, genetic, clinical, imaging biochemical data suggest a more complex aetiology. Here we review history weaknesses hypothesis in view new evidence obtained anti-amyloid antibodies. These indicate treatments either no or uncertain effect on cognition. Despite importance definition argue point playing minor aetiological role. We also discuss suggesting concerted activity many pathogenic factors propose evolving multi-factor models will better underpin search effective strategies treat disease.

Язык: Английский

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APOE4 homozygosity represents a distinct genetic form of Alzheimer’s disease

Nature Medicine, Год журнала: 2024, Номер 30(5), С. 1284 - 1291

Опубликована: Май 1, 2024

Язык: Английский

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Implications of Gut Microbiota in Neurodegenerative Diseases

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Фев. 14, 2022

The morbidity associated with neurodegenerative diseases (NDs) is increasing, posing a threat to the mental and physical quality of life humans. crucial effect microbiota on brain physiological processes mediated through bidirectional interaction, termed as gut–brain axis (GBA), which being investigated in studies. Many clinical laboratory trials have indicated importance development NDs via various microbial molecules that transmit from gut across GBA or nervous system. In this review, we summarize implications ND, will be beneficial for understanding etiology progression may turn help developing ND interventions treatments these diseases.

Язык: Английский

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Glial Cell-Mediated Neuroinflammation in Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(18), С. 10572 - 10572

Опубликована: Сен. 12, 2022

Alzheimer's disease (AD) is a progressive neurodegenerative disorder; it the most common cause of dementia and has no treatment. It characterized by two pathological hallmarks, extracellular deposits amyloid beta (Aβ) intraneuronal Neurofibrillary tangles (NFTs). Yet, those hallmarks do not explain full pathology seen with AD, suggesting involvement other mechanisms. Neuroinflammation could offer another explanation for progression disease. This review provides an overview recent advances on role immune cells' microglia astrocytes in neuroinflammation. In become reactive several mechanisms leading to release proinflammatory cytokines that further neuronal damage. We then provide updates neuroinflammation diagnostic markers investigational therapeutics currently clinical trials target

Язык: Английский

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Genome-wide association studies for Alzheimer’s disease: bigger is not always better

Brain Communications, Год журнала: 2022, Номер 4(3)

Опубликована: Май 2, 2022

As the size of genome-wide association studies increase, number associated trait loci identified inevitably increase. One welcomes this if it allows better delineation pathways to disease and increases accuracy genetic prediction risk through polygenic score analysis. However, there are several problems in continuing increase analysis 'Alzheimer's disease'. In review, we have systematically assessed history Alzheimer's studies, including their sample sizes, age selection/assessment criteria cases controls heritability explained by these studies. We observe that nearly all earlier now part current addition, latest include (i) only a small fraction (∼10%) clinically screened controls, substituting for them population-based samples which younger than cases, (ii) around 50% fact 'proxy dementia cases'. consequence, more genes field finds, less they explain. highlight potential caveats situation creates discuss some consequences occurring when translating newest study results into basic research and/or clinical practice.

Язык: Английский

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Exercise suppresses neuroinflammation for alleviating Alzheimer’s disease

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Март 19, 2023

Abstract Alzheimer’s disease (AD) is a chronic neurodegenerative disease, with the characteristics of neurofibrillary tangle (NFT) and senile plaque (SP) formation. Although great progresses have been made in clinical trials based on relevant hypotheses, these studies are also accompanied by emergence toxic side effects, it an urgent task to explore underlying mechanisms for benefits prevent treat AD. Herein, animal experiments few trials, neuroinflammation AD characterized long-term activation pro-inflammatory microglia NOD-, LRR- pyrin domain-containing protein 3 (NLRP3) inflammasomes. Damaged signals from periphery within brain continuously activate microglia, thus resulting constant source inflammatory responses. The response exacerbates endoplasmic reticulum oxidative stress which triggers microglia-dependent immune responses, ultimately leading occurrence deterioration In this review, we systematically summarized sorted out that exercise ameliorates directly indirectly regulating central nervous system promoting hippocampal neurogenesis provide new direction exploring activity

Язык: Английский

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Piperidine Derivatives: Recent Advances in Synthesis and Pharmacological Applications

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(3), С. 2937 - 2937

Опубликована: Фев. 2, 2023

Piperidines are among the most important synthetic fragments for designing drugs and play a significant role in pharmaceutical industry. Their derivatives present more than twenty classes of pharmaceuticals, as well alkaloids. The current review summarizes recent scientific literature on intra- intermolecular reactions leading to formation various piperidine derivatives: substituted piperidines, spiropiperidines, condensed piperidinones. Moreover, applications natural piperidines were covered, latest advances discovery biological evaluation potential containing moiety. This is designed help both novice researchers taking their first steps this field experienced scientists looking suitable substrates synthesis biologically active piperidines.

Язык: Английский

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