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Journal of Alzheimer's Disease : JAD 2020Mitochondria perform many essential cellular functions including energy production, calcium homeostasis, transduction of metabolic and stress signals, and mediating cell... (Review)
Review
Mitochondria perform many essential cellular functions including energy production, calcium homeostasis, transduction of metabolic and stress signals, and mediating cell survival and death. Maintaining viable populations of mitochondria is therefore critical for normal cell function. The selective disposal of damaged mitochondria, by a pathway known as mitophagy, plays a key role in preserving mitochondrial integrity and quality. Mitophagy reduces the formation of reactive oxygen species and is considered as a protective cellular process. Mitochondrial dysfunction and deficits of mitophagy have important roles in aging and especially in neurodegenerative disorders such as Alzheimer's disease (AD). Targeting mitophagy pathways has been suggested to have potential therapeutic effects against AD. In this review, we aim to briefly discuss the emerging concepts on mitophagy, molecular regulation of the mitophagy process, current mitophagy detection methods, and mitophagy dysfunction in AD. Finally, we will also briefly examine the stimulation of mitophagy as an approach for attenuating neurodegeneration in AD.
Topics: Alzheimer Disease; Animals; Humans; Mitochondria; Mitophagy
PubMed: 33285629
DOI: 10.3233/JAD-191258 -
The Journal of Prevention of... 2023Blood-brain barrier (BBB) disruption is an early event in the development of Alzheimer's disease. It precedes extracellular deposition of amyloid-β in senile plaques...
Blood-brain barrier (BBB) disruption is an early event in the development of Alzheimer's disease. It precedes extracellular deposition of amyloid-β in senile plaques and blood vessel walls, the intracellular accumulation of neurofibrillary tangles containing phosphorylated tau protein, microglial activation, and neuronal cell death. BBB disruption allows the coagulation protein fibrinogen to leak from the blood into the brain, where it is converted by thrombin cleavage into fibrin and deposits in the parenchyma and CNS vessels. Fibrinogen cleavage by thrombin exposes a cryptic epitope termed P2 which can bind CD11b and CD11c on microglia, macrophages and dendritic cells and trigger an inflammatory response toxic to neurons. Indeed, genetic and pharmacological evidence demonstrates a causal role for fibrin in innate immune cell activation and the development of neurodegenerative diseases. The P2 inflammatory epitope is spatially and compositionally distinct from the coagulation epitope on fibrin. Mouse monoclonal antibody 5B8, which targets the P2 epitope without interfering with the clotting process, has been shown to reduce neurodegeneration and neuroinflammation in animal models of Alzheimer's disease and multiple sclerosis. The selectivity and efficacy of this anti-human fibrin-P2 antibody in animal models supports the development of a monoclonal antibody drug targeting fibrin P2 for the treatment of neurodegenerative diseases. THN391 is a humanized, affinity-matured antibody which has a 100-fold greater affinity for fibrin P2 and improved development properties compared to the parental 5B8 antibody. It is currently in a Phase 1 clinical trial.
Topics: Mice; Animals; Humans; Alzheimer Disease; Fibrin; Thrombin; Neurodegenerative Diseases; Antibodies, Monoclonal; Fibrinogen; Immunotherapy; Epitopes
PubMed: 37874085
DOI: 10.14283/jpad.2023.105 -
Biomolecules Feb 2022Alzheimer's disease (AD) incidence is increasing worldwide at an alarming rate. Considering this increase, prevention efforts, stemming from scientific research, health... (Review)
Review
Alzheimer's disease (AD) incidence is increasing worldwide at an alarming rate. Considering this increase, prevention efforts, stemming from scientific research, health education, and public policies, are critical. Clinical studies evidenced that healthy lifestyles along with natural multitarget and disease-modifying agents have a preventative impact on AD or mitigate symptoms in diagnosed patients. The pathological alterations of AD start 30 years before symptoms, and it is essential to develop the capacity to detect those changes. In this regard, molecular biomarkers that detect early pathological manifestations are helpful. Based on markers data, early preventive interventions could reduce more than 40% of AD cases. Protective actions include exercise, shown to induce neurogenesis, cognitive stimulation, intellectual-social activity, and nutrition among others. Mediterranean diet, preprobiotics, and nutraceuticals containing bioactive molecules with antioxidant and anti-inflammatory properties are relevant. Antiprotein aggregation molecules whose mechanisms were described are important. Anti-inflammatory agents with anti-aggregation properties that help to control cognitive impairment, include quercetin, biocurcumin, rosemarinic acid, and Andean . Anthocyanidins, e.g., delphinidin, malvidin, and natural flavonoids, are also included. Quercetin and hydroxy-tyrosol are antiaging molecules and could have anti-AD properties. We emphasize the relevance of nutraceuticals as a main actor in the prevention and/or control of dementia and particularly AD.
Topics: Alzheimer Disease; Antioxidants; Cognitive Dysfunction; Diet, Mediterranean; Dietary Supplements; Humans
PubMed: 35204750
DOI: 10.3390/biom12020249 -
Journal of Alzheimer's Disease : JAD 2024
Topics: Alzheimer Disease; Humans; Genomics; Proteomics; Biomedical Research; Metabolomics
PubMed: 38640162
DOI: 10.3233/JAD-240272 -
Advances in Experimental Medicine and... 2020Alzheimer's disease (AD) was first described and diagnosed by Dr. Alois Alzheimer in 1906 (Hippius and Neundorfer, Dialogues Clin Neurosc 5:101-108, 2003). According to... (Review)
Review
Alzheimer's disease (AD) was first described and diagnosed by Dr. Alois Alzheimer in 1906 (Hippius and Neundorfer, Dialogues Clin Neurosc 5:101-108, 2003). According to World Health Organization (WHO), AD is the most common cause of dementia, accounting for as many as 60-70% of senile dementia cases and affecting 47.5 million people worldwide (data from 2015) (Dementia Fact Sheet No 362. http://who.int/mediacentre/factsheets/fs362/en/ ). The median survival time after the onset of dementia ranges from 3.3 to 11.7 years (Todd et al. Int J Geriatr Psychiatry 28:1109-1124, 2013). AD is characterized as a severe, chronic, incurable, and progressive neurodegenerative disorder, associated with memory loss and cognition impairment accompanied by abnormal behavior and personality changes (Godyn et al. Pharmacol Rep 68:127-138, 2016). AD is characterized by neuronal death, which usually correlates with the appearance of key neuropathological changes, including acetylcholine deficiency, glutamate excitotoxicity, extracellular deposition of β-amyloid (Aβ plaques), intracellular neurofibrillary tangles by hyperphosphorylated tau protein deposits, neuroinflammation, and widespread neuronal loss (Godyn et al. Pharmacol Rep 68:127-138, 2016; Graham et al. Annu Rev. Med 68:413-430, 2017). The discovery of the degeneration of cholinergic neurons and the reduction of acetylcholine levels in postmortem studies of patients resulted in the use of drugs that leads to the increase of acetylcholine levels in brain (Dubois et al. Lacet Neurol 13:614-629, 2014). At present there is no preventative or curative treatment that interferes with the development of the disease. However, in recent years progress was made in the development of cholinergic drugs which have a positive effect on disease progression. Nowadays, specific drugs that can inhibit the enzyme that degrades acetylcholine are used. The development of new effective drugs involves a difficult and time-consuming process, accompanied by a very high failure rate. In the absence of effective therapies, the estimated number of people with dementia will reach 115 to 131, five million by 2050 (Dubois et al. Lacet Neurol 13:614-629, 2014; Cummings et al. Alzheimers Res Ther 6:37, 2014). Novel therapies and new targets required for developing more effective drugs for the treatment of AD patients are urgently needed.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Humans; Neurofibrillary Tangles; Plaque, Amyloid; tau Proteins
PubMed: 32468465
DOI: 10.1007/978-3-030-32633-3_15 -
Zoological Research Nov 2023Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder that leads to cognitive impairment and memory loss. Emerging evidence suggests that... (Review)
Review
Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder that leads to cognitive impairment and memory loss. Emerging evidence suggests that autophagy plays an important role in the pathogenesis of AD through the regulation of amyloid-beta (Aβ) and tau metabolism, and that autophagy dysfunction exacerbates amyloidosis and tau pathology. Therefore, targeting autophagy may be an effective approach for the treatment of AD. Animal models are considered useful tools for investigating the pathogenic mechanisms and therapeutic strategies of diseases. This review aims to summarize the pathological alterations in autophagy in representative AD animal models and to present recent studies on newly discovered autophagy-stimulating interventions in animal AD models. Finally, the opportunities, difficulties, and future directions of autophagy targeting in AD therapy are discussed.
Topics: Animals; Alzheimer Disease; Amyloid beta-Peptides; Autophagy; Models, Animal
PubMed: 37963840
DOI: 10.24272/j.issn.2095-8137.2023.294 -
Journal of Alzheimer's Disease : JAD 2023The Journal of Alzheimer's Disease (JAD) is already an established forum for cutting-edge science as well as ethical reflection. But I argue that beyond science and...
The Journal of Alzheimer's Disease (JAD) is already an established forum for cutting-edge science as well as ethical reflection. But I argue that beyond science and ethics, JAD is also a forum for philosophy in science, and that interdisciplinary researchers asking innovative questions about AD should publish their reflections and findings in JAD.
Topics: Humans; Alzheimer Disease; Philosophy
PubMed: 37522211
DOI: 10.3233/JAD-230407 -
Journal of Alzheimer's Disease : JAD 2021Alzheimer's disease (AD) is the most common and devastating neurodegenerative condition worldwide, characterized by the aggregation of amyloid-β and phosphorylated tau... (Review)
Review
Alzheimer's disease (AD) is the most common and devastating neurodegenerative condition worldwide, characterized by the aggregation of amyloid-β and phosphorylated tau protein, and is accompanied by a progressive loss of learning and memory. A healthy nervous system is endowed with synaptic plasticity, among others neural plasticity mechanisms, allowing structural and physiological adaptations to changes in the environment. This neural plasticity modification sustains learning and memory, and behavioral changes and is severely affected by pathological and aging conditions, leading to cognitive deterioration. This article reviews critical aspects of AD neurodegeneration as well as therapeutic approaches that restore neural plasticity to provide functional recoveries, including environmental enrichment, physical exercise, transcranial stimulation, neurotrophin involvement, and direct electrical stimulation of the amygdala. In addition, we report recent behavioral results in Octodon degus, a promising natural model for the study of AD that naturally reproduces the neuropathological alterations observed in AD patients during normal aging, including neuronal toxicity, deterioration of neural plasticity, and the decline of learning and memory.
Topics: Activities of Daily Living; Alzheimer Disease; Animals; Exercise; Humans; Neuronal Plasticity; Neurons; Recovery of Function; Transcranial Direct Current Stimulation
PubMed: 33459642
DOI: 10.3233/JAD-201178 -
Journal of Alzheimer's Disease : JAD 2023
Topics: Humans; Aged; Alzheimer Disease
PubMed: 36710685
DOI: 10.3233/JAD-230016 -
Current Aging Science Aug 2022There is considerable empirical evidence that unequivocally points to loneliness as a modifiable risk factor for the development of Alzheimer's disease and other related... (Review)
Review
There is considerable empirical evidence that unequivocally points to loneliness as a modifiable risk factor for the development of Alzheimer's disease and other related dementias. With the emergence of the COVID-19 pandemic and the resulting lockdown and social distancing, there has been a renewed interest in studying this topic. The present review examines the links between loneliness and Alzheimer's disease, with particular emphasis on the mechanisms common to both conditions.
Topics: Alzheimer Disease; COVID-19; Communicable Disease Control; Humans; Loneliness; Pandemics; Risk Factors
PubMed: 35249519
DOI: 10.2174/1874609815666220304195049