Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies

Nature Reviews Neurology, Journal Year: 2019, Volume and Issue: 15(9), P. 501 - 518

Published: July 31, 2019

Language: Английский

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Alzheimer’s Disease: Treatment Strategies and Their Limitations

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(22), P. 13954 - 13954

Published: Nov. 12, 2022

Alzheimer’s disease (AD) is the most frequent case of neurodegenerative and becoming a major public health problem all over world. Many therapeutic strategies have been explored for several decades; however, there still no curative treatment, priority remains prevention. In this review, we present an update on clinical physiological phase AD spectrum, modifiable non-modifiable risk factors treatment with focus prevention strategies, then research models used in AD, followed by discussion limitations. The methods can significantly slow evolution are currently best strategy possible before advanced stages disease. Indeed, current drug treatments only symptomatic effects, disease-modifying not yet available. Drug delivery to central nervous system complex process represents challenge developing preventive strategies. Studies underway test new techniques facilitate bioavailability molecules brain. After deep study literature, find use soft nanoparticles, particular nanoliposomes exosomes, as innovative approach reducing solving problems brain bioavailability. show promising role exosomes smart systems able penetrate blood–brain barrier target tissues. Finally, different administration neurological disorders discussed. One intranasal which should be preclinical studies diseases.

Language: Английский

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Spheroids as a Type of Three-Dimensional Cell Cultures—Examples of Methods of Preparation and the Most Important Application

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(17), P. 6225 - 6225

Published: Aug. 28, 2020

Cell cultures are very important for testing materials and drugs, in the examination of cell biology special mechanisms. The most popular models culture two-dimensional (2D) as monolayers, but this does not mimic natural environment. Cells mostly deprived cell–cell cell–extracellular matrix interactions. A much better vitro model is three-dimensional (3D) culture. Because many lines have ability to self-assemble, one 3D culturing method produce spheroids. There several systems cells spheroids, e.g., hanging drop, scaffolds hydrogels, these their applications drug nanoparticles testing, disease modeling. In paper we would like present methods preparation spheroids general emphasize applications.

Language: Английский

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APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Nov. 2, 2020

Abstract APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) APOE ε3/ε3 or ε4/ε4 genotype from individuals either normal cognition AD dementia. Cerebral organoids patients carrying show greater apoptosis and decreased synaptic integrity. While patient-derived have increased levels of Aβ phosphorylated tau compared to healthy subject-derived organoids, exacerbates pathology in both organoids. Transcriptomics analysis by RNA-sequencing reveals that are an enhancement stress granules disrupted RNA metabolism. Importantly, isogenic conversion APOE3 attenuates -related phenotypes patients. Together, our study human iPSC-organoids recapitulates suggests degenerative pathways contributing pathogenesis.

Language: Английский

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The complexity of Alzheimer’s disease: an evolving puzzle

Physiological Reviews, Journal Year: 2021, Volume and Issue: 101(3), P. 1047 - 1081

Published: Jan. 21, 2021

The history of Alzheimer's disease (AD) started in 1907, but we needed to wait until the end century identify components pathological hallmarks and genetic subtypes formulate first pathogenic hypothesis. Thanks biomarkers new technologies, concept AD then rapidly changed from a static view an amnestic dementia presenium biological entity that could be clinically manifested as normal cognition or different types. What is clearly emerging studies heterogeneous each aspect, such amyloid composition, tau distribution, relation between tau, clinical symptoms, background, thus it probably impossible explain with single process. scientific approach suffers chronological mismatches clinical, pathological, technological data, causing difficulty conceiving diagnostic gold standards creating models for drug discovery screening. A recent mathematical computer-based offers opportunity study real life provide point final missing pieces puzzle.

Language: Английский

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Neuronal hyperexcitability in Alzheimer’s disease: what are the drivers behind this aberrant phenotype?

Translational Psychiatry, Journal Year: 2022, Volume and Issue: 12(1)

Published: June 22, 2022

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to loss of cognitive abilities and ultimately, death. With no cure available, limited treatments mostly focus on symptom management. Identifying early changes in the course may provide new therapeutic targets halt or reverse progression. Clinical studies have shown that cortical hippocampal hyperactivity are feature shared by patients stages disease, progressing hypoactivity during later neurodegeneration. The exact mechanisms causing neuronal excitability not fully characterized; however, animal cell models provided insights into some factors involved this phenotype. In review, we summarize evidence for over AD onset progression molecular underpinning these differences. Specifically, discuss contributors aberrant excitability, including abnormal levels intracellular Ca 2+ glutamate, pathological amyloid β (Aβ) tau, genetic risk factors, APOE , impaired inhibitory interneuron glial function. light recent research indicating hyperexcitability could be predictive marker dysfunction, further argue phenotype leveraged improve diagnosis treatment AD, present potential future development.

Language: Английский

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Advancement in the modelling and therapeutics of Parkinson’s disease

Journal of Chemical Neuroanatomy, Journal Year: 2020, Volume and Issue: 104, P. 101752 - 101752

Published: Jan. 26, 2020

Language: Английский

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OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome

Cell stem cell, Journal Year: 2019, Volume and Issue: 24(6), P. 908 - 926.e8

Published: May 23, 2019

Language: Английский

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Neuropathogenesis-on-chips for neurodegenerative diseases

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 12, 2024

Abstract Developing diagnostics and treatments for neurodegenerative diseases (NDs) is challenging due to multifactorial pathogenesis that progresses gradually. Advanced in vitro systems recapitulate patient-like pathophysiology are emerging as alternatives conventional animal-based models. In this review, we explore the interconnected pathogenic features of different types ND, discuss general strategy modelling NDs using a microfluidic chip, introduce organoid-on-a-chip next advanced relevant model. Lastly, overview how these models being applied academic industrial drug development. The integration chips, stem cells, biotechnological devices promises provide valuable insights biomedical research developing diagnostic therapeutic solutions NDs.

Language: Английский

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

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: May 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.

Language: Английский

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