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Molecules (Basel, Switzerland) Oct 2021Huperzine A (HupA), an alkaloid found in the club moss , has been used for centuries in Chinese folk medicine to treat dementia. The effects of this alkaloid have been... (Review)
Review
Huperzine A (HupA), an alkaloid found in the club moss , has been used for centuries in Chinese folk medicine to treat dementia. The effects of this alkaloid have been attributed to its ability to inhibit the cholinergic enzyme acetylcholinesterase (AChE), acting as an acetylcholinesterase inhibitor (AChEI). The biological functions of HupA have been studied both in vitro and in vivo, and its role in neuroprotection appears to be a good therapeutic candidate for Alzheimer´s disease (AD). Here, we summarize the neuroprotective effects of HupA on AD, with an emphasis on its interactions with different molecular signaling avenues, such as the Wnt signaling, the pre- and post-synaptic region mechanisms (synaptotagmin, neuroligins), the amyloid precursor protein (APP) processing, the amyloid-β peptide (Aβ) accumulation, and mitochondrial protection. Our goal is to provide an integrated overview of the molecular mechanisms through which HupA affects AD.
Topics: Acetylcholinesterase; Alkaloids; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Humans; Huperzia; Molecular Structure; Neuroprotective Agents; Sesquiterpenes; Signal Transduction
PubMed: 34770940
DOI: 10.3390/molecules26216531 -
Molecular Psychiatry Jan 2020Alzheimer's disease is a devastating neurodegenerative disorder with no cure. Countless promising therapeutics have shown efficacy in rodent Alzheimer's disease models... (Review)
Review
Alzheimer's disease is a devastating neurodegenerative disorder with no cure. Countless promising therapeutics have shown efficacy in rodent Alzheimer's disease models yet failed to benefit human patients. While hope remains that earlier intervention with existing therapeutics will improve outcomes, it is becoming increasingly clear that new approaches to understand and combat the pathophysiology of Alzheimer's disease are needed. Human induced pluripotent stem cell (iPSC) technologies have changed the face of preclinical research and iPSC-derived cell types are being utilized to study an array of human conditions, including neurodegenerative disease. All major brain cell types can now be differentiated from iPSCs, while increasingly complex co-culture systems are being developed to facilitate neuroscience research. Many cellular functions perturbed in Alzheimer's disease can be recapitulated using iPSC-derived cells in vitro, and co-culture platforms are beginning to yield insights into the complex interactions that occur between brain cell types during neurodegeneration. Further, iPSC-based systems and genome editing tools will be critical in understanding the roles of the numerous new genes and mutations found to modify Alzheimer's disease risk in the past decade. While still in their relative infancy, these developing iPSC-based technologies hold considerable promise to push forward efforts to combat Alzheimer's disease and other neurodegenerative disorders.
Topics: Alzheimer Disease; Brain; Cell Differentiation; Humans; Induced Pluripotent Stem Cells; Models, Biological; Neurodegenerative Diseases; Neurons
PubMed: 31391546
DOI: 10.1038/s41380-019-0468-3 -
Redox Biology Dec 2023Oxygen metabolism abnormality plays a crucial role in the pathogenesis of Alzheimer's disease (AD) via several mechanisms, including hypoxia, oxidative stress, and... (Review)
Review
Oxygen metabolism abnormality plays a crucial role in the pathogenesis of Alzheimer's disease (AD) via several mechanisms, including hypoxia, oxidative stress, and mitochondrial dysfunction. Hypoxia condition usually results from living in a high-altitude habitat, cardiovascular and cerebrovascular diseases, and chronic obstructive sleep apnea. Chronic hypoxia has been identified as a significant risk factor for AD, showing an aggravation of various pathological components of AD, such as amyloid β-protein (Aβ) metabolism, tau phosphorylation, mitochondrial dysfunction, and neuroinflammation. It is known that hypoxia and excessive hyperoxia can both result in oxidative stress and mitochondrial dysfunction. Oxidative stress and mitochondrial dysfunction can increase Aβ and tau phosphorylation, and Aβ and tau proteins can lead to redox imbalance, thus forming a vicious cycle and exacerbating AD pathology. Hyperbaric oxygen therapy (HBOT) is a non-invasive intervention known for its capacity to significantly enhance cerebral oxygenation levels, which can significantly attenuate Aβ aggregation, tau phosphorylation, and neuroinflammation. However, further investigation is imperative to determine the optimal oxygen pressure, duration of exposure, and frequency of HBOT sessions. In this review, we explore the prospects of oxygen metabolism in AD, with the aim of enhancing our understanding of the underlying molecular mechanisms in AD. Current research aimed at attenuating abnormalities in oxygen metabolism holds promise for providing novel therapeutic approaches for AD.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Oxygen; Neuroinflammatory Diseases; tau Proteins; Hypoxia
PubMed: 37956598
DOI: 10.1016/j.redox.2023.102955 -
Alzheimer's Research & Therapy Sep 2020Alzheimer's disease (AD) has been a devastating public health with the development of global aging. Approaches for reducing the current AD epidemic are becoming a... (Review)
Review
Alzheimer's disease (AD) has been a devastating public health with the development of global aging. Approaches for reducing the current AD epidemic are becoming a primary focus of human healthcare due to the lack of achieved lasting and complete remission strategies to treat AD with the characteristics of heterogeneity and complexity. Exosomes, which is the new emerging approach to intercellular communication, provide novel perspective on identified therapeutic strategies of AD. Mesenchymal stem cell-derived exosomes (MSC-exos) are emerging to be an appealing therapeutic tool for AD, with the donor-derived properties and the characteristics of minimal immunogenicity, effortless storage, nature delivery vehicles, and low risks of tumor formation based on the previous researches. In this review, we elaborate the mechanism of MSC-exos in the treatment of AD and discuss limitations in the clinical application.
Topics: Alzheimer Disease; Exosomes; Humans; Mesenchymal Stem Cells
PubMed: 32928293
DOI: 10.1186/s13195-020-00670-x -
Nutrients Jan 2021The microbiota-gut-brain axis plays an important role in the development of neurodegenerative diseases. Commensal and pathogenic enteric bacteria can influence brain and... (Review)
Review
The microbiota-gut-brain axis plays an important role in the development of neurodegenerative diseases. Commensal and pathogenic enteric bacteria can influence brain and immune system function by the production of lipopolysaccharides and amyloid. Dysbiosis of the intestinal microbiome induces local and consecutively systemic immune-mediated inflammation. Proinflammatory cytokines then trigger neuroinflammation and finally neurodegeneration. Immune-mediated oxidative stress can lead to a deficiency of vitamins and essential micronutrients. Furthermore, the wrong composition of gut microbiota might impair the intake and metabolization of nutrients. In patients with Alzheimer's disease (AD) significant alterations of the gut microbiota have been demonstrated. Standard Western diet, infections, decreased physical activity and chronic stress impact the composition and diversity of gut microbiota. A higher abundancy of "pro-inflammatory" gut microbiota goes along with enhanced systemic inflammation and neuroinflammatory processes. Thus, AD beginning in the gut is closely related to the imbalance of gut microbiota. Modulation of gut microbiota by Mediterranean diet, probiotics and curcumin can slow down cognitive decline and alter the gut microbiome significantly. A multi-domain intervention approach addressing underlying causes of AD (inflammation, infections, metabolic alterations like insulin resistance and nutrient deficiency, stress) appears very promising to reduce or even reverse cognitive decline by exerting positive effects on the gut microbiota.
Topics: Aged; Alzheimer Disease; Gastrointestinal Microbiome; Humans
PubMed: 33504065
DOI: 10.3390/nu13020361 -
International Journal of Molecular... Nov 2019While Alzheimer's disease (AD) classical diagnostic criteria rely on clinical data from a stablished symptomatic disease, newer criteria aim to identify the disease in... (Review)
Review
While Alzheimer's disease (AD) classical diagnostic criteria rely on clinical data from a stablished symptomatic disease, newer criteria aim to identify the disease in its earlier stages. For that, they incorporated the use of AD's specific biomarkers to reach a diagnosis, including the identification of Aβ and tau depositions, glucose hypometabolism, and cerebral atrophy. These biomarkers created a new concept of the disease, in which AD's main pathological processes have already taken place decades before we can clinically diagnose the first symptoms. Therefore, AD is now considered a dynamic disease with a gradual progression, and dementia is its final stage. With that in mind, new models were proposed, considering the orderly increment of biomarkers and the disease as a continuum, or the variable time needed for the disease's progression. In 2011, the National Institute on Aging and the Alzheimer's Association (NIA-AA) created separate diagnostic recommendations for each stage of the disease continuum-preclinical, mild cognitive impairment, and dementia. However, new scientific advances have led them to create a unifying research framework in 2018 that, although not intended for clinical use as of yet, is a step toward shifting the focus from the clinical symptoms to the biological alterations and toward changing the future diagnostic and treatment possibilities. This review aims to discuss the role of biomarkers in the onset of AD.
Topics: Alzheimer Disease; Biomarkers; Humans; Risk Factors
PubMed: 31698826
DOI: 10.3390/ijms20225536 -
Stem Cell Reviews and Reports Feb 2022During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study mechanisms of human neural development, disease modeling, and drug... (Review)
Review
During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study mechanisms of human neural development, disease modeling, and drug discovery in vitro. Especially in the field of Alzheimer's disease (AD), where this treatment is lacking, tremendous effort has been put into the investigation of molecular mechanisms behind this disease using induced pluripotent stem cell-based models. Numerous of these studies have found either novel regulatory mechanisms that could be exploited to develop relevant drugs for AD treatment or have already tested small molecules on in vitro cultures, directly demonstrating their effect on amelioration of AD-associated pathology. This review thus summarizes currently used differentiation strategies of induced pluripotent stem cells towards neuronal and glial cell types and cerebral organoids and their utilization in modeling AD and potential drug discovery.
Topics: Alzheimer Disease; Humans; Induced Pluripotent Stem Cells; Neural Stem Cells; Neurons; Organoids
PubMed: 35107767
DOI: 10.1007/s12015-021-10254-3 -
Journal of Alzheimer's Disease : JAD 2023Diet is an important nonpharmacological risk-modifying factor for Alzheimer's disease (AD). The approaches used here to assess diet's role in the risk of AD include... (Review)
Review
Diet is an important nonpharmacological risk-modifying factor for Alzheimer's disease (AD). The approaches used here to assess diet's role in the risk of AD include multi-country ecological studies, prospective and cross-sectional observational studies, and laboratory studies. Ecological studies have identified fat, meat, and obesity from high-energy diets as important risk factors for AD and reported that AD rates peak about 15-20 years after national dietary changes. Observational studies have compared the Western dietary pattern with those of the Dietary Approaches to Stop Hypertension (DASH), Mediterranean (MedDi), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets. Those studies identified AD risk factors including higher consumption of saturated and total fats, meat, and ultraprocessed foods and a lower risk of AD with higher consumption of fruits, legumes, nuts, omega-3 fatty acids, vegetables, and whole grains. Diet-induced factors associated with a significant risk of AD include inflammation, insulin resistance, oxidative stress, elevated homocysteine, dietary advanced glycation end products, and trimethylamine N-oxide. The molecular mechanisms by which dietary bioactive components and specific foods affect risk of AD are discussed. Given most countries' entrenched food supply systems, the upward trends of AD rates would be hard to reverse. However, for people willing and able, a low-animal product diet with plenty of anti-inflammatory, low-glycemic load foods may be helpful.
Topics: Humans; Alzheimer Disease; Cross-Sectional Studies; Prospective Studies; Diet; Risk Factors
PubMed: 37955087
DOI: 10.3233/JAD-230418 -
Alzheimer's & Dementia : the Journal of... Jan 2023Chitinase-3-like protein 1 (CHI3L1/YKL-40) has long been known as a biomarker for early detection of neuroinflammation and disease diagnosis of Alzheimer's disease (AD)....
Chitinase-3-like protein 1 (CHI3L1/YKL-40) has long been known as a biomarker for early detection of neuroinflammation and disease diagnosis of Alzheimer's disease (AD). In the brain, CHI3L1 is primarily provided by astrocytes and heralds the reactive, neurotoxic state triggered by inflammation and other stress signals. However, how CHI3L1 acts in neuroinflammation or how it contributes to AD and relevant neurodegenerative conditions remains unknown. In peripheral tissues, our group and others have uncovered that CHI3L1 is a master regulator for a wide range of injury and repair events, including the innate immunity pathway that resembles the neuroinflammation process governed by microglia and astrocytes. Based on assessment of current knowledge regarding CHI3L1 biology, we hypothesize that CHI3L1 functions as a signaling molecule mediating distinct neuroinflammatory responses in brain cells and misfunctions to precipitate neurodegeneration. We also recommend future research directions to validate such assertions for better understanding of disease mechanisms.
Topics: Humans; Alzheimer Disease; Chitinase-3-Like Protein 1; Chitinases; Neuroinflammatory Diseases; Inflammation
PubMed: 35234337
DOI: 10.1002/alz.12612 -
Journal of Alzheimer's Disease : JAD 2022An infectious etiology of Alzheimer's disease has been postulated for decades. It remains unknown whether SARS-CoV-2 viral infection is associated with increased risk...
An infectious etiology of Alzheimer's disease has been postulated for decades. It remains unknown whether SARS-CoV-2 viral infection is associated with increased risk for Alzheimer's disease. In this retrospective cohort study of 6,245,282 older adults (age ≥65 years) who had medical encounters between 2/2020-5/2021, we show that people with COVID-19 were at significantly increased risk for new diagnosis of Alzheimer's disease within 360 days after the initial COVID-19 diagnosis (hazard ratio or HR:1.69, 95% CI: 1.53-1.72), especially in people age ≥85 years and in women. Our findings call for research to understand the underlying mechanisms and for continuous surveillance of long-term impacts of COVID-19 on Alzheimer's disease.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; COVID-19; COVID-19 Testing; Female; Humans; Retrospective Studies; SARS-CoV-2
PubMed: 35912749
DOI: 10.3233/JAD-220717