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PLoS Pathogens Jun 2020
Review
Topics: Alzheimer Disease; Herpesviridae; Herpesviridae Infections; Humans
PubMed: 32555685
DOI: 10.1371/journal.ppat.1008575 -
International Journal of Molecular... Sep 2021Cellular identity is determined through complex patterns of gene expression. Chromatin, the dynamic structure containing genetic information, is regulated through... (Review)
Review
Cellular identity is determined through complex patterns of gene expression. Chromatin, the dynamic structure containing genetic information, is regulated through epigenetic modulators, mainly by the histone code. One of the main challenges for the cell is maintaining functionality and identity, despite the accumulation of DNA damage throughout the aging process. Replicative cells can remain in a senescent state or develop a malign cancer phenotype. In contrast, post-mitotic cells such as pyramidal neurons maintain extraordinary functionality despite advanced age, but they lose their identity. This review focuses on tau, a protein that protects DNA, organizes chromatin, and plays a crucial role in genomic stability. In contrast, tau cytosolic aggregates are considered hallmarks of Alzheimer´s disease (AD) and other neurodegenerative disorders called tauopathies. Here, we explain AD as a phenomenon of chromatin dysregulation directly involving the epigenetic histone code and a progressive destabilization of the tau-chromatin interaction, leading to the consequent dysregulation of gene expression. Although this destabilization could be lethal for post-mitotic neurons, tau protein mediates profound cellular transformations that allow for their temporal survival.
Topics: Alzheimer Disease; Chromatin; DNA; DNA Damage; Epigenesis, Genetic; Genomic Instability; Histone Code; Humans; Nucleosomes; Phosphorylation; Time Factors; tau Proteins
PubMed: 34638632
DOI: 10.3390/ijms221910283 -
Journal of Alzheimer's Disease : JAD 2020Dementia has been described as the greatest global health challenge in the 21st Century on account of longevity gains increasing its incidence, escalating health and... (Review)
Review
BACKGROUND
Dementia has been described as the greatest global health challenge in the 21st Century on account of longevity gains increasing its incidence, escalating health and social care pressures. These pressures highlight ethical, social, and political challenges about healthcare resource allocation, what health improvements matter to patients, and how they are measured. This study highlights the complexity of the ethical landscape, relating particularly to the balances that need to be struck when allocating resources; when measuring and prioritizing outcomes; and when individual preferences are sought.
OBJECTIVE
Health outcome prioritization is the ranking in order of desirability or importance of a set of disease-related objectives and their associated cost or risk. We analyze the complex ethical landscape in which this takes place in the most common dementia, Alzheimer's disease.
METHODS
Narrative review of literature published since 2007, incorporating snowball sampling where necessary. We identified, thematized, and discussed key issues of ethical salience.
RESULTS
Eight areas of ethical salience for outcome prioritization emerged: 1) Public health and distributive justice, 2) Scarcity of resources, 3) Heterogeneity and changing circumstances, 4) Knowledge of treatment, 5) Values and circumstances, 6) Conflicting priorities, 7) Communication, autonomy and caregiver issues, and 8) Disclosure of risk.
CONCLUSION
These areas highlight the difficult balance to be struck when allocating resources, when measuring and prioritizing outcomes, and when individual preferences are sought. We conclude by reflecting on how tools in social sciences and ethics can help address challenges posed by resource allocation, measuring and prioritizing outcomes, and eliciting stakeholder preferences.
Topics: Alzheimer Disease; Delivery of Health Care; Humans; Outcome Assessment, Health Care
PubMed: 32716354
DOI: 10.3233/JAD-191300 -
Scientific Reports Jan 2023Alzheimer's disease is the most common form of dementia. Notwithstanding the huge investments in drug development, only one disease-modifying treatment has been recently...
Alzheimer's disease is the most common form of dementia. Notwithstanding the huge investments in drug development, only one disease-modifying treatment has been recently approved. Here we present a single-cell-led systems biology pipeline for the identification of drug repurposing candidates. Using single-cell RNA sequencing data of brain tissues from patients with Alzheimer's disease, genome-wide association study results, and multiple gene annotation resources, we built a multi-cellular Alzheimer's disease molecular network that we leveraged for gaining cell-specific insights into Alzheimer's disease pathophysiology and for the identification of drug repurposing candidates. Our computational approach pointed out 54 candidate drugs, mainly targeting MAPK and IGF1R signaling pathways, which could be further evaluated for their potential as Alzheimer's disease therapy.
Topics: Humans; Alzheimer Disease; Drug Repositioning; Genome-Wide Association Study; Systems Biology
PubMed: 36604493
DOI: 10.1038/s41598-023-27420-x -
Journal of Alzheimer's Disease : JAD 2021Neurodegenerative diseases called tauopathies, such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease, among... (Review)
Review
Neurodegenerative diseases called tauopathies, such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease, among others, are characterized by the pathological processing and accumulation of tau protein. AD is the most prevalent neurodegenerative disease and is characterized by two lesions: neurofibrillary tangles (NFTs) and neuritic plaques. The presence of NFTs in the hippocampus and neocortex in early and advanced stages, respectively, correlates with the patient's cognitive deterioration. So far, no drugs can prevent, decrease, or limit neuronal death due to abnormal pathological tau accumulation. Among potential non-pharmacological treatments, physical exercise has been shown to stimulate the development of stem cells (SCs) and may be useful in early stages. However, this does not prevent neuronal death from the massive accumulation of NFTs. In recent years, SCs therapies have emerged as a promising tool to repopulate areas involved in cognition in neurodegenerative diseases. Unfortunately, protocols for SCs therapy are still being developed and the mechanism of action of such therapy remains unclear. In this review, we show the advances and limitations of SCs therapy. Finally, we provide a critical analysis of its clinical use for AD.
Topics: Alzheimer Disease; Amyloid; Government Regulation; Hippocampus; Humans; Neocortex; Neurofibrillary Tangles; Plaque, Amyloid; Stem Cells; tau Proteins
PubMed: 34633316
DOI: 10.3233/JAD-200863 -
Annals of Nutrition & Metabolism 2022The rapid worldwide increase in the incidence of Alzheimer's disease is associated with changing nutrition patterns. Recently, some articles have highlighted the link... (Review)
Review
BACKGROUND
The rapid worldwide increase in the incidence of Alzheimer's disease is associated with changing nutrition patterns. Recently, some articles have highlighted the link between Alzheimer's disease and dietary cholesterol. It was found that elevated levels of some of its fractions in the brain and circulation affect metabolism.
SUMMARY
Previous studies have considered the relationship between Alzheimer's disease and oxidized cholesterol molecules in the brain. To date, there are limited data available on the relationship between oxidized cholesterol in the brain and Alzheimer's disease. There is a link between a diet high in cholesterol and its oxidized forms, leading to hypercholesterolemia, which is one of significant risk factors of dementia, and Alzheimer's disease. Oxidized cholesterol can be absorbed in the small intestine and cross the blood-brain barrier, leading to increased inflammation and endogenous oxidative process. Animal-origin foods are sources of oxidized cholesterol, with cholesterol oxidation beginning already after slaughter and occurring during storage and processing.
KEY MESSAGES
High-heat food preparation and storage of cooked products in the refrigerator followed by subsequent heating may significantly increase the amount of oxidized cholesterol products. Therefore, a diet low in cholesterol oxidation products and high in plants with antioxidative properties seems to be most preventable and should be implemented as early as possible.
Topics: Alzheimer Disease; Animals; Brain; Cholesterol; Diet; Humans; Oxysterols
PubMed: 35545012
DOI: 10.1159/000520514 -
Journal of Alzheimer's Disease : JAD 2023Alzheimer's disease (AD) is considered to be the most common neurodegenerative disease, with clinical symptoms encompassing progressive memory loss and cognitive... (Review)
Review
Alzheimer's disease (AD) is considered to be the most common neurodegenerative disease, with clinical symptoms encompassing progressive memory loss and cognitive impairment. Necroptosis is a form of programmed necrosis that promotes cell death and neuroinflammation, which further mediates the pathogenesis of several neurodegenerative diseases, especially AD. Current evidence has strongly suggested that necroptosis is activated in AD brains, resulting in neuronal death and cognitive impairment. We searched the PubMed database, screening all articles published before September 28, 2022 related to necroptosis in the context of AD pathology. The keywords in the search included: "necroptosis", "Alzheimer's disease", "signaling pathways", "Aβ", Aβo", "Tau", "p-Tau", "neuronal death", "BBB damage", "neuroinflammation", "microglia", "mitochondrial dysfunction", "granulovacuolar degeneration", "synaptic loss", "axonal degeneration", "Nec-1", "Nec-1s", "GSK872", "NSA", "OGA", "RIPK1", "RIPK3", and "MLKL". Results show that necroptosis has been involved in multiple pathological processes of AD, including amyloid-β aggregation, Tau accumulation, neuronal death, and blood-brain barrier damage, etc. More importantly, existing research on AD necroptosis interventions, including drug intervention and potential gene targets, as well as its current clinical development status, was discussed. Finally, the issues pertaining to necroptosis in AD were presented. Accordingly, this review may provide further insight into clinical perspectives and challenges for the future treatment of AD by targeting the necroptosis pathway.
Topics: Humans; Alzheimer Disease; Neurodegenerative Diseases; Necrosis; Apoptosis; Amyloid beta-Peptides
PubMed: 36463451
DOI: 10.3233/JAD-220809 -
European Journal of Nuclear Medicine... Dec 2019Neuroinflammation, as defined by the activation of microglia and astrocytes, has emerged in the last years as a key element of the pathogenesis of neurodegenerative... (Review)
Review
Neuroinflammation, as defined by the activation of microglia and astrocytes, has emerged in the last years as a key element of the pathogenesis of neurodegenerative diseases based on genetic findings and preclinical and human studies. This has raised the need for new methodologies to assess and follow glial activation in patients, prompting the development of PET ligands for molecular imaging of glial cells and novel structural MRI and DTI tools leading to a multimodal approach. The present review describes the recent advancements in microglia and astrocyte biology in the context of health, ageing, and Alzheimer's disease, the most common dementia worldwide. The review further delves in molecular imaging discussing the challenges associated with past and present targets, including conflicting findings, and finally, presenting novel methodologies currently explored to improve our in vivo knowledge of the neuroinflammatory patterns in Alzheimer's disease. With glial cell activation as a potential therapeutic target in neurodegenerative diseases, the translational research between cell biologists, chemists, physicists, radiologists, and neurologists should be strengthened.
Topics: Alzheimer Disease; Astrocytes; Cognitive Dysfunction; Humans; Inflammation; Neuroimaging; Receptors, GABA
PubMed: 31396666
DOI: 10.1007/s00259-019-04462-w -
Journal of Alzheimer's Disease : JAD 2023In clinical trials, lecanemab and donanemab showed statistically significant yet marginal slowdown of Alzheimer's disease (AD)-associated cognitive decline. This could...
In clinical trials, lecanemab and donanemab showed statistically significant yet marginal slowdown of Alzheimer's disease (AD)-associated cognitive decline. This could be due to their sub-optimal design and/or deployment; alternatively, their limited efficiency could be intrinsic. Distinguishing between the two is of great importance considering the acute need of efficient AD therapy and tremendous resources being invested in its pursuit. The present study analyzes the mode of operation of lecanemab and donanemab within the framework of recently proposed Amyloid Cascade Hypothesis 2.0 and concludes that the second possibility is correct. It suggests that substantial improvement of the efficiency of these drugs in symptomatic AD is unlikely and proposes the alternative therapeutic strategy.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Amyloid; Amyloidogenic Proteins
PubMed: 37212119
DOI: 10.3233/JAD-230164 -
BioMed Research International 2021Alzheimer's disease is a neurodegenerative disorder that is caused by the accumulation of beta-amyloid plaques in the brain. Currently, there is no definitive cure... (Review)
Review
Alzheimer's disease is a neurodegenerative disorder that is caused by the accumulation of beta-amyloid plaques in the brain. Currently, there is no definitive cure available to treat Alzheimer's disease. The available medication in the market has the ability to only slow down its progression. However, nanotechnology has shown its superiority that can be applied for medical usage and it has a great potential in the therapy of Alzheimer's disease, specifically in the disease diagnosis and providing an alternative approach to treat Alzheimer's disease. This is done by increasing the efficiency of drug delivery by penetrating and overcoming the blood-brain barrier. Having said that, there are limitations that need to be further investigated and researched in order to minimize the adverse effects and potential toxicity and to improve drug bioavailability. The recent advances in the treatment of Alzheimer's disease using nanotechnology include the regeneration of stem cells, nanomedicine, and neuroprotection. In this review, we will discuss the advancement of nanotechnology which helps in the diagnosis and treatment of neurodegenerative disorders such as Alzheimer's disease as well as its challenges.
Topics: Alzheimer Disease; Animals; Drug Delivery Systems; Genetic Therapy; Humans; Immunotherapy; Nanoparticles; Nanotechnology
PubMed: 34285915
DOI: 10.1155/2021/5550938