scholarly journals Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 383 ◽  
Author(s):  
Yam Nath Paudel ◽  
Efthalia Angelopoulou ◽  
Christina Piperi ◽  
Iekhsan Othman ◽  
Khurram Aamir ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
High Mobility ◽  
Health Concern ◽  
Hmgb1 Protein ◽  
Therapeutic Targeting ◽  
Beneficial Effects ◽  
Molecular Pattern ◽  
Glycation End Products

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.

scholarly journals Probiotics: An Adjuvant therapy for D-Galactose induced Alzheimer's disease

2017 ◽  
Vol 1 (1) ◽  
pp. 30-33 ◽  
Author(s):  
Varshil Mehta ◽  
Kavya Bhatt ◽  
Nimit Desai ◽  
Mansi Naik
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Brain Regions ◽  
Health Concern ◽  
Major Health ◽  
Acetyl Choline ◽  
Glycation End Products ◽  
Anti Oxidant

Alzheimer’s disease (AD) is a chronic and slowly progressing neurodegenerative disorder which has become a major health concern worldwide. The literature has shown that oxidative stress is one of the most important risk factors behind the cause of AD. Oxidative stress often leads to the production of Reactive Oxygen Species (ROS). D-Galactose, a physiological nutrient and reducing sugar, non-enzymatically reacts with amines of amino acids in proteins and peptides to form Advanced Glycation End products which activate its receptors coupled to Biochemical pathways that stimulate free radical production and induces mitochondrial dysfunction which damages the neuron intracellularly. High dosage of D-Galactose also suppresses the expression of nerve growth factors and its associated protein which results in the degeneration of nerve cells and reduction of acetylcholine levels in brain regions. This article put forwards the advantages of using Lactic Acid Bacteria (Probiotics) possessing anti-oxidant properties and which produces Acetyl Choline against D-Galactose induced Alzheimer’s disease.

Beneficial Effects of Choline Alphoscerate on Amyloid-β Neurotoxicity in an In vitro Model of Alzheimer’s Disease

2021 ◽  
Vol 18 ◽  
Author(s):  
Chiara Burgaletto ◽  
Giulia Di Benedetto ◽  
Antonio Munafò ◽  
Renato Bernardini ◽  
Giuseppina Cantarella
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Vitro Model ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Health Concern ◽  
Noic Acid ◽  
Beneficial Effects ◽  
Vitro Model

Background: Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder characterized by cognitive impairment, which represents an urgent public health concern. Given the worldwide impact of AD, there is a compelling need for effective therapies to slow down or halt this disorder. Objective: Choline alphoscerate (α-GPC) represents a potentially effective cholinergic neurotrans- mission enhancing agent with an interesting clinical profile in cognitive dysfunctions improve- ment, although only scanty data are available about the mechanisms underlying such beneficial ef- fects. Method: The SH-SY5Y neuronal cell line, differentiated for 1 week with 10 μm of all-trans-reti- noic acid (RA), to achieve a switch towards a cholinergic phenotype, was used as an in vitro model of AD. SH-SY5Y cells were pre-treated for 1h with α-GPC (100nM) and treated for 72 h with Aβ25-35 (10μM). Results: α-GPC was able to antagonize Aβ25-35 mediated neurotoxicity and attenuate the Aβ-in- duced phosphorylation of the Tau protein. Moreover, α-GPC exerted its beneficial effects by em- ploying the NGF/TrkA system, knocked down in AD and, consequently, by sustaining the expres- sion level of synaptic vesicle proteins, such as synaptophysin. Conclusion: Taken together, our data suggest that α-GPC can have a role in neuroprotection in the course of toxic challenges with Aβ. Thus, a deeper understanding of the mechanism underlying its beneficial effect, could provide new insights into potential future pharmacological applications of its functional cholinergic enhancement, with the aim to mitigate AD and could represent the basis for innovative therapy.

The Role of High Mobility Group Box 1 (HMGB1) in Neurodegeneration: A Systematic Review

2022 ◽  
Vol 20 ◽  
Author(s):  
Fathimath Zaha Ikram ◽  
Alina Arulsamy ◽  
Thaarvena Retinasamy ◽  
Mohd. Farooq Shaikh
Keyword(s):  
Systematic Review ◽  
Tissue Injury ◽  
High Mobility ◽  
High Mobility Group ◽  
Hmgb1 Protein ◽  
Toll Like Receptor 4 ◽  
Neuroinflammatory Response ◽  
Molecular Pattern ◽  
Glycation End Products

Background: High mobility group box 1 (HMGB1) protein is a damage-associated molecular pattern (DAMP) molecule that plays an important role in the repair and regeneration of tissue injury. It also acts as a pro-inflammatory cytokine through the activation of toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), to elicit the neuroinflammatory response. HMGB1 may aggravate several cellular responses which may lead to pathological inflammation and cellular death. Thus, there have been a considerable amount of research into the pathological role of HMGB1 in diseases. However, whether the mechanism of action of HMGB1 is similar in all neurodegenerative disease pathology remains to be determined. Objective: Therefore, this systematic review aimed to critically evaluate and elucidate the role of HMGB1 in the pathology of neurodegeneration based on the available literature. Methods: A comprehensive literature search was performed on four databases; EMBASE, PubMed, Scopus, and CINAHL Plus. Results: A total of 85 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that HMGB1 levels were found elevated in most neurodegeneration except in Huntington’s disease and Spinocerebellar ataxia, where the levels were found decreased. This review also showcased that HMGB1 may act on distinctive pathways to elicit its pathological response leading to the various neurodegeneration processes/diseases. Conclusion: While there have been promising findings in HMGB1 intervention research, further studies may still be required before any HMGB1 intervention may be recommended as a therapeutic target for neurodegenerative diseases.

scholarly journals Energy homeostasis deregulation is attenuated by TUDCA treatment in streptozotocin-induced Alzheimer’s disease mice model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lucas Zangerolamo ◽  
Carina Solon ◽  
Gabriela M. Soares ◽  
Daiane F. Engel ◽  
Licio A. Velloso ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Body Weight ◽  
Food Intake ◽  
Energy Homeostasis ◽  
Neurodegenerative Disorder ◽  
Mice Model ◽  
Appetite Control ◽  
Beneficial Effects ◽  
Lower Body Weight

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. While cognitive deficits remain the major manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown beneficial effects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin-induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the effects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz + TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz + TUDCA mice reduced fluorescence and gene expression of inflammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz + TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals.

NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS–STING

2021 ◽  
Vol 118 (37) ◽  
pp. e2011226118
Author(s):  
Yujun Hou ◽  
Yong Wei ◽  
Sofie Lautrup ◽  
Beimeng Yang ◽  
Yue Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Damage ◽  
Cellular Senescence ◽  
Neurodegenerative Disorder ◽  
Mutant Mice ◽  
Beneficial Effects ◽  
Markers Of Inflammation ◽  
Model Of Alzheimer’S Disease ◽  
Synaptic Functions

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of AD, but their interplay is not clear. Nicotinamide adenine dinucleotide (NAD+) is an important metabolite in all human cells in which it is pivotal for multiple processes including DNA repair and mitophagy, both of which are impaired in AD neurons. Here, we report that levels of NAD+ are reduced and markers of inflammation increased in the brains of APP/PS1 mutant transgenic mice with beta-amyloid pathology. Treatment of APP/PS1 mutant mice with the NAD+ precursor nicotinamide riboside (NR) for 5 mo increased brain NAD+ levels, reduced expression of proinflammatory cytokines, and decreased activation of microglia and astrocytes. NR treatment also reduced NLRP3 inflammasome expression, DNA damage, apoptosis, and cellular senescence in the AD mouse brains. Activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are associated with DNA damage and senescence. cGAS–STING elevation was observed in the AD mice and normalized by NR treatment. Cell culture experiments using microglia suggested that the beneficial effects of NR are, in part, through a cGAS–STING-dependent pathway. Levels of ectopic (cytoplasmic) DNA were increased in APP/PS1 mutant mice and human AD fibroblasts and down-regulated by NR. NR treatment induced mitophagy and improved cognitive and synaptic functions in APP/PS1 mutant mice. Our findings suggest a role for NAD+ depletion-mediated activation of cGAS–STING in neuroinflammation and cellular senescence in AD.

scholarly journals Approaches to Optimizing Dantrolene Neuroprotection for the Treatment of Alzheimer's Disease

2020 ◽  
Vol 17 (4) ◽  
pp. 324-328
Author(s):  
Matan B. Abou ◽  
Liang Sun ◽  
Huafeng Wei
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Current Status ◽  
Beneficial Effects ◽  
Incidence And Mortality ◽  
High Incidence ◽  
The Central Nervous System ◽  
Dose Dependent

Alzheimer’s Disease (AD), a neurodegenerative disorder with high incidence and mortality, is leading its way to the top of the list of the deadliest diseases without an effective disease-modifying drug. Ca2+ dysregulation, specifically abnormal release of Ca2+ via over activated ryanodine receptor (RyR), has been increasingly considered as an alternative upstream mechanism in AD pathology. Consequently, dantrolene, a RyR antagonist and FDA approved drug to treat malignant hyperthermia and chronic muscle spasms, has been shown to ameliorate memory loss in AD transgenic mice. However, the inefficiency of dantrolene to pass the Blood Brain Barrier (BBB) and penetrate the Central Nervous System needs to be resolved, considering its dose-dependent neuroprotection in AD and other neurodegenerative diseases. In this mini-review, we will discuss the current status of dantrolene neuroprotection in AD treatment and a strategy to maximize its beneficial effects, such as intranasal administration of dantrolene.

scholarly journals Nutrition and the Risk of Alzheimer's Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Nan Hu ◽  
Jin-Tai Yu ◽  
Lin Tan ◽  
Ying-Li Wang ◽  
Lei Sun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dietary Patterns ◽  
Neurodegenerative Disorder ◽  
Epidemiological Studies ◽  
Health Concern ◽  
Modifiable Risk Factors ◽  
Public Health Concern ◽  
Randomized Controlled ◽  
Japanese Diet

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for the major cause of dementia, and the increasing worldwide prevalence of AD is a major public health concern. Increasing epidemiological studies suggest that diet and nutrition might be important modifiable risk factors for AD. Dietary supplementation of antioxidants, B vitamins, polyphenols, and polyunsaturated fatty acids are beneficial to AD, and consumptions of fish, fruits, vegetables, coffee, and light-to-moderate alcohol reduce the risk of AD. However, many of the results from randomized controlled trials are contradictory to that of epidemiological studies. Dietary patterns summarizing an overall diet are gaining momentum in recent years. Adherence to a healthy diet, the Japanese diet, and the Mediterranean diet is associated with a lower risk of AD. This paper will focus on the evidence linking many nutrients, foods, and dietary patterns to AD.

scholarly journals Natural Compounds for Alzheimer’s Disease Therapy: A Systematic Review of Preclinical and Clinical Studies

2019 ◽  
Vol 20 (9) ◽  
pp. 2313 ◽  
Author(s):  
Stephanie Andrade ◽  
Maria João Ramalho ◽  
Joana Angélica Loureiro ◽  
Maria do Carmo Pereira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Studies ◽  
Neurodegenerative Disorder ◽  
Natural Compounds ◽  
Continuous Increase ◽  
Beneficial Effects ◽  
Wide Range ◽  
Relevant Role ◽  
Preclinical And Clinical Studies

Alzheimer’s Disease (AD) is a neurodegenerative disorder related with the increase of age and it is the main cause of dementia in the world. AD affects cognitive functions, such as memory, with an intensity that leads to several functional losses. The continuous increase of AD incidence demands for an urgent development of effective therapeutic strategies. Despite the extensive research on this disease, only a few drugs able to delay the progression of the disease are currently available. In the last years, several compounds with pharmacological activities isolated from plants, animals and microorganisms, revealed to have beneficial effects for the treatment of AD, targeting different pathological mechanisms. Thus, a wide range of natural compounds may play a relevant role in the prevention of AD and have proven to be efficient in different preclinical and clinical studies. This work aims to review the natural compounds that until this date were described as having significant benefits for this neurological disease, focusing on studies that present clinical trials.

scholarly journals Role of Methylglyoxal in Alzheimer’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Cristina Angeloni ◽  
Laura Zambonin ◽  
Silvana Hrelia
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Advanced Glycation ◽  
Hyperphosphorylated Tau Protein ◽  
Glycation End Products ◽  
And Oxidative Stress ◽  
Endogenous Process

Alzheimer’s disease is the most common and lethal neurodegenerative disorder. The major hallmarks of Alzheimer’s disease are extracellular aggregation of amyloidβpeptides and, the presence of intracellular neurofibrillary tangles formed by precipitation/aggregation of hyperphosphorylated tau protein. The etiology of Alzheimer’s disease is multifactorial and a full understanding of its pathogenesis remains elusive. Some years ago, it has been suggested that glycation may contribute to both extensive protein cross-linking and oxidative stress in Alzheimer’s disease. Glycation is an endogenous process that leads to the production of a class of compounds known as advanced glycation end products (AGEs). Interestingly, increased levels of AGEs have been observed in brains of Alzheimer’s disease patients. Methylglyoxal, a reactive intermediate of cellular metabolism, is the most potent precursor of AGEs and is strictly correlated with an increase of oxidative stress in Alzheimer’s disease. Many studies are showing that methylglyoxal and methylglyoxal-derived AGEs play a key role in the etiopathogenesis of Alzheimer's disease.

scholarly journals Neuroprotective Potentials of Panax Ginseng Against Alzheimer’s Disease: A Review of Preclinical and Clinical Evidences

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Li ◽  
Qingxia Huang ◽  
Jinjin Chen ◽  
Hongyu Qi ◽  
Jiaqi Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Panax Ginseng ◽  
Neurodegenerative Disorder ◽  
Clinical Findings ◽  
Health Concern ◽  
Amyloid Formation ◽  
Neuroprotective Effects ◽  
Major Health ◽  
Prevention And Treatment

Alzheimer’s disease (AD), a neurodegenerative disorder, is a major health concern in the increasingly aged population worldwide. Currently, no clinically effective drug can halt the progression of AD. Panax ginseng C.A. Mey. is a well-known medicinal plant that contains ginsenosides, gintonin, and other components and has neuroprotective effects against a series of pathological cascades in AD, including beta-amyloid formation, neuroinflammation, oxidative stress, and mitochondrial dysfunction. In this review, we summarize the effects and mechanisms of these major components and formulas containing P. ginseng in neuronal cells and animal models. Moreover, clinical findings regarding the prevention and treatment of AD with P. ginseng or its formulas are discussed. This review can provide new insights into the possible use of ginseng in the prevention and treatment of AD.

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