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 Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease?

2020 ◽  
Vol 14 ◽  
Author(s):  
Antonio Munafò ◽  
Chiara Burgaletto ◽  
Giulia Di Benedetto ◽  
Marco Di Mauro ◽  
Rosaria Di Mauro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune System ◽  
Neurodegenerative Disorder ◽  
Drug Repositioning ◽  
Amyloid Β ◽  
Deep Understanding ◽  
Current Status ◽  
Age Related ◽  
Tnf Α

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder characterized by cognitive decline and by the presence of amyloid β plaques and neurofibrillary tangles in the brain. Despite recent advances in understanding its pathophysiological mechanisms, to date, there are no disease-modifying therapeutic options, to slow or halt the evolution of neurodegenerative processes in AD. Current pharmacological treatments only transiently mitigate the severity of symptoms, with modest or null overall improvement. Emerging evidence supports the concept that AD is affected by the impaired ability of the immune system to restrain the brain’s pathology. Deep understanding of the relationship between the nervous and the immune system may provide a novel arena to develop effective and safe drugs for AD treatment. Considering the crucial role of inflammatory/immune pathways in AD, here we discuss the current status of the immuno-oncological, immunomodulatory and anti-TNF-α drugs which are being used in preclinical studies or in ongoing clinical trials by means of the drug-repositioning approach.

Clinical course of Alzheimer’s disease

2011 ◽  
Author(s):  
Alberto Lleo ◽  
Rafael Blesa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Daily Living ◽  
Clinical Course ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Remote Memory ◽  
Initial Symptom ◽  
Delayed Recall ◽  
Age Related

• Alzheimer’s disease is an age-related neurodegenerative disorder, with onset usually in late life, characterized by cognitive impairment, a variety of behavioural symptoms, and restrictions in the activities of daily living• The initial symptom is episodic memory loss, in particular in delayed recall of visual and/or verbal material. Immediate and remote memory is usually preserved in early stages...

scholarly journals Influence of Woodsmoke Exposure on Molecular Mechanisms Underlying Alzheimer’s Disease: Existing Literature and Gaps in Our Understanding

2020 ◽  
Vol 13 ◽  
pp. 251686572095487
Author(s):  
Adam Schuller ◽  
Luke Montrose
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Air Pollution ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Ambient Air ◽  
The United States ◽  
Ambient Air Pollution ◽  
Current Status

Woodsmoke poses a significant health risk as a growing component of ambient air pollution in the United States. While there is a long history of association between woodsmoke exposure and diseases of the respiratory, circulatory, and cardiovascular systems, recent evidence has linked woodsmoke exposure to cognitive dysfunction, including Alzheimer’s disease dementia. Alzheimer’s disease is a progressive neurodegenerative disorder with largely idiopathic origins and no known cure. Here, we explore the growing body of literature which relates woodsmoke-generated and ambient air pollution particulate matter exposure to Alzheimer’s disease (AD) onset or exacerbation, in the context of an inflammation-centric view of AD. Epigenetic modifications, specifically changes in DNA methylation patterns, are well documented following woodsmoke exposure and have been shown to influence disease-favoring inflammatory cascades, induce oxidative stress, and modulate the immune response in vitro, in vivo, and in humans following exposure to air pollution. Though the current status of the literature does not allow us to draw definitive conclusions linking these events, this review highlights the need for additional work to fill gaps in our understanding of the directionality, causality, and susceptibility throughout the life course.

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.

scholarly journals Alzheimer’s disease: many failed trials, so where do we go from here?

2020 ◽  
Vol 68 (6) ◽  
pp. 1135-1140 ◽  
Author(s):  
Allison Bethanne Reiss ◽  
Amy D Glass ◽  
Thomas Wisniewski ◽  
Benjamin Wolozin ◽  
Irving H Gomolin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Current Knowledge ◽  
Memory Loss ◽  
Treatment Strategies ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Brain Disorder ◽  
The Central Nervous System ◽  
Progressive Cognitive Impairment

Alzheimer’s disease (AD) is a neurodegenerative brain disorder associated with relentlessly progressive cognitive impairment and memory loss. AD pathology proceeds for decades before cognitive deficits become clinically apparent, opening a window for preventative therapy. Imbalance of clearance and buildup of amyloid β and phosphorylated tau proteins in the central nervous system is believed to contribute to AD pathogenesis. However, multiple clinical trials of treatments aimed at averting accumulation of these proteins have yielded little success, and there is still no disease-modifying intervention. Here, we discuss current knowledge of AD pathology and treatment with an emphasis on emerging biomarkers and treatment strategies.

scholarly journals Article Commentary: Alzheimer's Disease, Diagnosis and the Need for Biomarkers

2008 ◽  
Vol 3 ◽  
pp. BMI.S682 ◽  
Author(s):  
Claudie Hooper ◽  
Simon Lovestone ◽  
Ricardo Sainz-Fuertes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Cost Effective ◽  
Predictive Biomarker ◽  
Disease Diagnosis ◽  
Response To Therapy ◽  
Histopathological Analysis

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of aging that presents with memory loss, disorientation, confusion and a reduction in cognitive ability. Although a definite diagnosis of the disorder can only be made post-mortem by histopathological analysis, a number of methods are currently available for the in vivo assessment of AD including psycho-metric tests and neuro-imaging. However, these clinical assessments are relatively nonspecific and imaging is very costly. Genetic testing can be performed if familial AD is suspected, although such cases represent a very small minority of total AD cases. Apolipoprotein E genotype provides a measure for analysing the risk of developing AD, but does not act as an absolute predictive biomarker for AD. Therefore there is a need for an accurate, universal, specific and cost-effective biomarker to facilitate not only ante-mortem diagnosis of AD, but also to allow progression of the disease and response to therapy to be monitored. This is the ultimate goal that our group is pursuing through the pan-European AddNeuroMed project.

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.

A Systematic Review on Donepezil-based Derivatives as Potential Cholinesterase Inhibitors for Alzheimer’s Disease

2019 ◽  
Vol 26 (30) ◽  
pp. 5625-5648 ◽  
Author(s):  
Jan Korabecny ◽  
Katarina Spilovska ◽  
Eva Mezeiova ◽  
Ondrej Benek ◽  
Radomir Juza ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Nmda Receptor Antagonist ◽  
Amyloid Burden ◽  
Ache Inhibitors ◽  
Intellectual Capacity ◽  
Β Amyloid

: Alzheimer’s Disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by memory loss, disorientation, and gradual deterioration of intellectual capacity. Its etiology has not been elucidated yet. To date, only one therapeutic approach has been approved for the treatment of AD. The pharmacotherapy of AD has relied on noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist - memantine, and acetylcholinesterase (AChE) inhibitors (AChEIs) - tacrine, donepezil, rivastigmine and galantamine. Donepezil was able to ameliorate the symptoms related to AD mainly via AChE, but also through reduction of β-amyloid burden. This review presents the overview of donepezilrelated compounds as potential anti-AD drugs developed on the basis of cholinergic hypothesis to act as solely AChE and butyrylcholinesterase (BChE) inhibitors.

Phosphorylation and Glycosylation of Amyloid-β Protein Precursor: The Relationship to Trafficking and Cleavage in Alzheimer’s Disease

2021 ◽  
pp. 1-21
Author(s):  
Xi-Jun Song ◽  
He-Yan Zhou ◽  
Yu-Ying Sun ◽  
Han-Chang Huang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein ◽  
Cleavage Enzyme ◽  
The Central Nervous System

Alzheimer’s disease (AD) is a neurodegenerative disorder in the central nervous system, and this disease is characterized by extracellular senile plaques and intracellular neurofibrillary tangles. Amyloid-β (Aβ) peptide is the main constituent of senile plaques, and this peptide is derived from the amyloid-β protein precursor (AβPP) through the successive cleaving by β-site AβPP-cleavage enzyme 1 (BACE1) and γ-secretase. AβPP undergoes the progress of post-translational modifications, such as phosphorylation and glycosylation, which might affect the trafficking and the cleavage of AβPP. In the recent years, about 10 phosphorylation sites of AβPP were identified, and they play complex roles in glycosylation modification and cleavage of AβPP. In this article, we introduced the transport and the cleavage pathways of AβPP, then summarized the phosphorylation and glycosylation sites of AβPP, and further discussed the links and relationship between phosphorylation and glycosylation on the pathways of AβPP trafficking and cleavage in order to provide theoretical basis for AD research.

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.

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