scholarly journals Sirtuins as Potential Therapeutic Targets for Mitigating Neuroinflammation Associated With Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Kurukulasooriya Kavindya Madushani Fernando ◽  
Yasanandana Supunsiri Wijayasinghe
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Activation ◽  
Neurodegenerative Disorder ◽  
Therapeutic Interventions ◽  
Cellular Processes ◽  
Dependent Protein ◽  
The Central Nervous System ◽  
Β Amyloid ◽  
With Memory

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which is associated with memory deficit and global cognitive decline. Age is the greatest risk factor for AD and, in recent years, it is becoming increasingly appreciated that aging-related neuroinflammation plays a key role in the pathogenesis of AD. The presence of β-amyloid plaques and neurofibrillary tangles are the primary pathological hallmarks of AD; defects which can then activate a cascade of molecular inflammatory pathways in glial cells. Microglia, the resident macrophages in the central nervous system (CNS), are the major triggers of inflammation; a response which is typically intended to prevent further damage to the CNS. However, persistent microglial activation (i.e., neuroinflammation) is toxic to both neurons and glia, which then leads to neurodegeneration. Growing evidence supports a central role for sirtuins in the regulation of neuroinflammation. Sirtuins are NAD+-dependent protein deacetylases that modulate a number of cellular processes associated with inflammation. This review examines the latest findings regarding AD-associated neuroinflammation, mainly focusing on the connections among the microglial molecular pathways of inflammation. Furthermore, we highlight the biology of sirtuins, and their role in neuroinflammation. Suppression of microglial activity through modulation of the sirtuin activity has now become a key area of research, where progress in therapeutic interventions may slow the progression of Alzheimer’s disease.

Strategies Targeting Soluble β-Amyloid Oligomers and their Application to Early Diagnosis of Alzheimer’s Disease

2020 ◽  
Vol 16 (12) ◽  
pp. 1132-1142 ◽  
Author(s):  
Fantian Zeng ◽  
Yuyan Li ◽  
Yungen Xu ◽  
Jian Yang ◽  
Zhengshi Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Diagnosis ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Therapeutic Interventions ◽  
Detection Methods ◽  
Fluorescence Probes ◽  
Amyloid Oligomers ◽  
Β Amyloid

Background: Alzheimer’s Disease (AD) is the most common neurodegenerative disorder, and it is still incurable. Early diagnosis and intervention are crucial for delaying the onset and progression of the disease. Mounting evidence indicates that the neurotoxic effects might be attributed to Soluble β-Amyloid Oligomers (SAβO). The SAβO are believed to be neurotoxic peptides more predominant than Aβ plaques in the early stage, and their key role in AD is self-evident. Unfortunately, identification of SAβO proves to be difficult due to their heterogeneous and transient nature. In spite of many obstacles, multiple techniques have recently been developed to target SAβO effectively. This review focuses on the recent progress in the approaches towards SAβO detection in order to shed some light on the future development of SAβO assays. Methods : Literatures were obtained from the following libraries: Web of Science, PubMed, EPO, SIPO, USPTO. Articles were critically reviewed based on their titles, abstracts, and contents. Results: A total of 85 papers are referenced in the review. Results are divided into three categories based on the types of detection methods: small molecule fluorescence probes, oligomer-specific antibodies and electrochemical biosensors. Finally, the improvements and challenges of these approaches applied in the early diagnosis of AD were discussed. Conclusion: This review article covers three kinds of strategies that could be translated into clinic practice and lead to earlier diagnosis and therapeutic interventions of AD.

scholarly journals The link between chronic pain and Alzheimer’s disease

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Song Cao ◽  
Daniel W. Fisher ◽  
Tain Yu ◽  
Hongxin Dong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chronic Pain ◽  
Animal Studies ◽  
Microglial Activation ◽  
The Elderly ◽  
Therapeutic Interventions ◽  
Affective Component ◽  
Inflammatory Activation ◽  
Improve Patient

Abstract Chronic pain often occurs in the elderly, particularly in the patients with neurodegenerative disorders such as Alzheimer’s disease (AD). Although studies indicate that chronic pain correlates with cognitive decline, it is unclear whether chronic pain accelerates AD pathogenesis. In this review, we provide evidence that supports a link between chronic pain and AD and discuss potential mechanisms underlying this connection based on currently available literature from human and animal studies. Specifically, we describe two intertwined processes, locus coeruleus noradrenergic system dysfunction and neuroinflammation resulting from microglial pro-inflammatory activation in brain areas mediating the affective component of pain and cognition that have been found to influence both chronic pain and AD. These represent a pathological overlap that likely leads chronic pain to accelerate AD pathogenesis. Further, we discuss potential therapeutic interventions targeting noradrenergic dysfunction and microglial activation that may improve patient outcomes for those with chronic pain and AD.

scholarly journals CX3CL1/CX3CR1 in Alzheimer’s Disease: A Target for Neuroprotection

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Peiqing Chen ◽  
Wenjuan Zhao ◽  
Yanjie Guo ◽  
Juan Xu ◽  
Ming Yin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Central Nervous System ◽  
Nervous System ◽  
Early Diagnosis ◽  
Vital Role ◽  
Therapeutic Interventions ◽  
Chemokine Ligand ◽  
The Central Nervous System ◽  
Receptor Cx3cr1

CX3C chemokine ligand 1 (CX3CL1) is an intriguing chemokine belonging to the CX3C family. CX3CL1 is secreted by neurons and plays an important role in modulating glial activation in the central nervous system after binding to its sole receptor CX3CR1 which mainly is expressed on microglia. Emerging data highlights the beneficial potential of CX3CL1-CX3CR1 in the pathogenesis of Alzheimer’s disease (AD), a common progressive neurodegenerative disease, and in the progression of which neuroinflammation plays a vital role. Even so, the importance of CX3CL1/CX3CR1 in AD is still controversial and needs further clarification. In this review, we make an attempt to present a concise map of CX3CL1-CX3CR1 associated with AD to find biomarkers for early diagnosis or therapeutic interventions.

scholarly journals Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention

2021 ◽  
Vol 15 ◽  
Author(s):  
Guimei Zhang ◽  
Zicheng Wang ◽  
Huiling Hu ◽  
Meng Zhao ◽  
Li Sun
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Interventions ◽  
Tau Pathology ◽  
Age Related ◽  
Amyloid Accumulation ◽  
Pathophysiological Role ◽  
Inflammatory Drugs ◽  
Β Amyloid

Alzheimer’s disease (AD) is one of the most common types of age-related dementia worldwide. In addition to extracellular amyloid plaques and intracellular neurofibrillary tangles, dysregulated microglia also play deleterious roles in the AD pathogenesis. Numerous studies have demonstrated that unbridled microglial activity induces a chronic neuroinflammatory environment, promotes β-amyloid accumulation and tau pathology, and impairs microglia-associated mitophagy. Thus, targeting microglia may pave the way for new therapeutic interventions. This review provides a thorough overview of the pathophysiological role of the microglia in AD and illustrates the potential avenues for microglia-targeted therapies, including microglial modification, immunoreceptors, and anti-inflammatory drugs.

scholarly journals Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer’s Disease Model Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Afzal Misrani ◽  
Sidra Tabassum ◽  
Qingwei Huo ◽  
Sumaiya Tabassum ◽  
Jinxiang Jiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Morphology ◽  
Therapeutic Interventions ◽  
Early Event ◽  
Mitochondrial Morphology

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.

scholarly journals From hybrids to new scaffolds: the latest medicinal chemistry goals in multi-target directed ligands for Alzheimer’s disease

2020 ◽  
Vol 18 ◽  
Author(s):  
Jazmín Alarcón-Espósito ◽  
Michael Mallea ◽  
Julio Rodríguez-Lavado
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Mental Deterioration ◽  
Common Causes ◽  
Β Amyloid ◽  
The One ◽  
And Function ◽  
Shed Light ◽  
Multitarget Therapy

: Alzheimer’s disease (AD) is a chronic, progressive, and fatal neurodegenerative disorder affecting cognition, behavior, and function, being one of the most common causes of mental deterioration in elderly people. Once thought as being just developed because of β amyloid depositions or neurofibrillary Tau tangles, during the last decades, numerous ADrelated targets have been established, the multifactorial nature of AD became evident. In this context, the one drug-one target paradigm has resulted to be inefficient in facing AD and other disorders with complex etiology, opening the field for the emergence of the multitarget approach. In this review, we highlight the recent advances within this area, emphasizing in hybridization tools of well-known chemical scaffolds endowed with pharmacological properties concerning AD, such as curcumin-, resveratrol-, chromone- and indole-. We focus mainly on well stablished and incipient AD therapeutic targets, AChE, BuChE, MAOs, β-amyloid deposition, 5-HT4 and Serotonin transporter, with the aim to shed light about new insights in the AD multitarget therapy.

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.

scholarly journals Amyloidosis in Alzheimer’s Disease: The Toxicity of Amyloid Beta (Aβ), Mechanisms of Its Accumulation and Implications of Medicinal Plants for Therapy

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Anchalee Prasansuklab ◽  
Tewin Tencomnao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Herbal Medicines ◽  
Underlying Disease ◽  
Current Therapy ◽  
The Central Nervous System ◽  
Number Of Individuals

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to memory deficits and death. While the number of individuals with AD is rising each year due to the longer life expectancy worldwide, current therapy can only somewhat relieve the symptoms of AD. There is no proven medication to cure or prevent the disease, possibly due to a lack of knowledge regarding the molecular mechanisms underlying disease pathogenesis. Most previous studies have accepted the “amyloid hypothesis,” in which the neuropathogenesis of AD is believed to be triggered by the accumulation of the toxic amyloid beta (Aβ) protein in the central nervous system (CNS). Lately, knowledge that may be critical to unraveling the hidden pathogenic pathway of AD has been revealed. This review concentrates on the toxicity of Aβand the mechanism of accumulation of this toxic protein in the brain of individuals with AD and also summarizes recent advances in the study of these accumulation mechanisms together with the role of herbal medicines that could facilitate the development of more effective therapeutic and preventive strategies.

scholarly journals Zinc transporters in Alzheimer’s disease

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Yingshuo Xu ◽  
Guiran Xiao ◽  
Li Liu ◽  
Minglin Lang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Critical Role ◽  
Zinc Transporters ◽  
Protein Levels ◽  
Zinc Chelator ◽  
The Central Nervous System ◽  
Novel Therapeutic Strategies

AbstractAlzheimer’s disease (AD) is the most devastating neurodegenerative disorder. Due to the increase in population and longevity, incidence will triple by the middle of the twenty-first century. So far, no treatment has prevented or reversed the disease. More than 20 years of multidisciplinary studies have shown that brain zinc dyshomeostasis may play a critical role in AD progression, which provides encouraging clues for metal-targeted therapies in the treatment of AD. Unfortunately, the pilot clinical application of zinc chelator and/or ionophore strategy, such as the use of quinoline-based compounds, namely clioquinol and PBT2, has not yet been successful. The emerging findings revealed a list of key zinc transporters whose mRNA or protein levels were abnormally altered at different stages of AD brains. Furthermore, specifically modulating the expression of some of the zinc transporters in the central nervous system through genetic methods slowed down or prevented AD progression in animal models, resulting in significantly improved cognitive performance, movement, and prolonged lifespan. Although the underlying molecular mechanisms are not yet fully understood, it shed new light on the treatment or prevention of the disease. This review considers recent advances regarding AD, zinc and zinc transporters, recapitulating their relationships in extending our current understanding of the disease amelioration effects of zinc transport proteins as potential therapeutic targets to cure AD, and it may also provide new insights to identify novel therapeutic strategies for ageing and other neurodegenerative diseases, such as Huntington’s and Parkinson’s disease.

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