scholarly journals A2A Adenosine Receptor as a Potential Biomarker and a Possible Therapeutic Target in Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2344
Author(s):  
Stefania Gessi ◽  
Tino Emanuele Poloni ◽  
Giulia Negro ◽  
Katia Varani ◽  
Silvia Pasquini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adenosine Receptor ◽  
Therapeutic Target ◽  
Calcium Influx ◽  
Glutamate Release ◽  
Receptor Activation ◽  
A2a Adenosine Receptor ◽  
Potential Biomarker ◽  
A2a Receptor

Alzheimer’s disease (AD) is one of the most common neurodegenerative pathologies. Its incidence is in dramatic growth in Western societies and there is a need of both biomarkers to support the clinical diagnosis and drugs for the treatment of AD. The diagnostic criteria of AD are based on clinical data. However, it is necessary to develop biomarkers considering the neuropathology of AD. The A2A receptor, a G-protein coupled member of the P1 family of adenosine receptors, has different functions crucial for neurodegeneration. Its activation in the hippocampal region regulates synaptic plasticity and in particular glutamate release, NMDA receptor activation and calcium influx. Additionally, it exerts effects in neuroinflammation, regulating the secretion of pro-inflammatory cytokines. In AD patients, its expression is increased in the hippocampus/entorhinal cortex more than in the frontal cortex, a phenomenon not observed in age-matched control brains, indicating an association with AD pathology. It is upregulated in peripheral blood cells of patients affected by AD, thus reflecting its increase at central neuronal level. This review offers an overview on the main AD biomarkers and the potential role of A2A adenosine receptor as a new marker and therapeutic target.

A2A Adenosine Receptor Antagonists in Neurodegenerative Diseases

2021 ◽  
Vol 28 ◽  
Author(s):  
Stefania Merighi ◽  
Pier Andrea Borea ◽  
Katia Varani ◽  
Fabrizio Vincenzi ◽  
Kenneth A. Jacobson ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Rational Design ◽  
Symptomatic Relief ◽  
Clinical Signs ◽  
Receptor Activation ◽  
Amyloid Peptide ◽  
Receptor Antagonists ◽  
A2a Adenosine Receptor ◽  
A2a Adenosine Receptors ◽  
A2a Receptor

Background: Alzheimer's disease (AD) is the most common form of dementia worldwide, with approximately 6 million American cases in 2020. The clinical signs of AD include cognitive dysfunction, apathy, anxiety and neuropsychiatric signs, and pathogenetic mechanisms that involve amyloid peptide-β extracellular accumulation and tau hyperphosphorylation. Unfortunately, current drugs to treat AD can provide only symptomatic relief but are not disease-modifying molecules able to revert AD progression. The endogenous modulator adenosine, through A2A receptor activation, plays a role in synaptic loss and neuroinflammation, which are crucial for cognitive impairment and memory damage. Objective: In this review, recent advances covering A2A adenosine receptor antagonists will be extensively reviewed, providing a base for the rational design of future A2A inhibitors. Method: Herein, the literature on A2A adenosine receptors and their role in synaptic plasticity and neuroinflammation as well as the effects of A2A antagonism in animal models of AD and in humans are reviewed. Furthermore, current chemical and structure-based strategies are presented. Results : Caffeine, the most widely consumed natural product stimulant and an A2A antagonist, improves human memory. Similarly, synthetic A2A receptor antagonists, as described in this review, may provide a means to fight AD. Conclusion: This review highlights the clinical potential of A2A adenosine receptor antagonists as a novel approach to treat patients with AD.

scholarly journals An Open Question: Is the A2A Adenosine Receptor a Novel Target for Alzheimer’s Disease Treatment?

2021 ◽  
Vol 12 ◽  
Author(s):  
Stefania Merighi ◽  
Tino Emanuele Poloni ◽  
Lucia Pelloni ◽  
Silvia Pasquini ◽  
Katia Varani ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adenosine Receptor ◽  
Disease Treatment ◽  
A2a Adenosine Receptor ◽  
Novel Target ◽  
Open Question

scholarly journals Guanosine monophosphate reductase 1 is a potential therapeutic target for Alzheimer’s disease

2017 ◽  
Author(s):  
Hongde Liu ◽  
Kun Luo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adenosine Receptor ◽  
Therapeutic Target ◽  
Neurodegenerative Disorder ◽  
Guanosine Monophosphate ◽  
Expression Level ◽  
Amyloid Accumulation ◽  
Elevated Expression ◽  
Approved Drugs

AbstractAlzheimer’s disease (AD) is a severe neurodegenerative disorder. Identification of differentially expressed genes in AD would help to find biomarker and therapeutic target. Here, we carried out an analysis to identify the age-independent and AD-specific genes. We found that genes MET, WIF1 and NPTX2 are down regulated in AD. WIF1 and MET are in signaling of WNT and MET, regulating the activity of GSK3β, thus in AD. Importantly, we found gene GMPR shows a gradual increase in AD progress. A logistic model based on GMPR exhibits a good capacity in classifying AD cases. GMPR’s product GMPR1 links with AMPK and adenosine receptor pathways, thus associating phosphorylation of Tau in AD. This allows GMPR1 to be a therapeutic target. Therefore, we screened five possible inhibitors to GMPR1 by docking GMPR1 with 1174 approved drugs. Among them, lumacaftor is ideal due to its high affinity and light molecular weight. We then tested the effect of lumacaftor on AD model mice. After twenty days of oral administration, β-Amyloid accumulation is slowed down and phosphorylation of Tau is almost eliminated in the treated mice, showing a satisfying effect. In conclusion, the elevated expression level of GMPR tightly associates with AD progress and leads to AD phenotype probably through AMPK and adenosine receptor pathways; and one of therapeutic strategies is to inhibit GMPR’s product with lumacaftor.Significance StatementWe found the elevated expression level of GMPR tightly associates with AD progress and leads to AD phenotype probably through AMPK and adenosine receptor pathways; and the therapeutic strategy targeting GMPR1 with lumacaftor shows a satisfying result.

Memapsin 2, a drug target for Alzheimer's disease

2003 ◽  
Vol 70 ◽  
pp. 213-220 ◽  
Author(s):  
Gerald Koelsch ◽  
Robert T. Turner ◽  
Lin Hong ◽  
Arun K. Ghosh ◽  
Jordan Tang
Keyword(s):  
Crystal Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transition State ◽  
Amyloid Precursor Protein ◽  
Therapeutic Target ◽  
Drug Target ◽  
Aspartic Protease ◽  
Precursor Protein ◽  
Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

scholarly journals Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

2021 ◽  
Vol 22 (7) ◽  
pp. 3330
Author(s):  
Mehdi Eshraghi ◽  
Aida Adlimoghaddam ◽  
Amir Mahmoodzadeh ◽  
Farzaneh Sharifzad ◽  
Hamed Yasavoli-Sharahi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Target ◽  
Neurological Disorder ◽  
Inflammatory Cells ◽  
Disease Pathogenesis ◽  
Current Review ◽  
The Brain ◽  
Comprehensive Discussion

Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including am-yloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflammation interact in a bidirectional manner. In the current review, we briefly discussed an overview on autophagy and mitophagy in AD and then provided a comprehensive discussion on the role of these pathways in microglia and their involvement in AD pathogenesis.

MicroRNA-4422-5p as a Negative Regulator of Amyloidogenic Secretases: A Potential Biomarker for Alzheimer’s disease

Neuroscience ◽  
2021 ◽  
Author(s):  
Seyedeh Nazanin Hajjari ◽  
Saeed Sadigh-Eteghad ◽  
Dariush Shanehbandi ◽  
Shahram Teimourian ◽  
Ali Shahbazi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Negative Regulator ◽  
Potential Biomarker

scholarly journals Proteins and microRNAs are differentially expressed in tear fluid from patients with Alzheimer’s disease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Aidan Kenny ◽  
Eva M. Jiménez-Mateos ◽  
María Ascensión Zea-Sevilla ◽  
Alberto Rábano ◽  
Pablo Gili-Manzanaro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Unmet Need ◽  
Cost Effective ◽  
Specific Protein ◽  
Tear Fluid ◽  
Initiation Factor ◽  
Non Invasive ◽  
A Genome ◽  
Potential Biomarker

Abstract Alzheimer’s disease (AD) is characterized by a progressive loss of neurons and cognitive functions. Therefore, early diagnosis of AD is critical. The development of practical and non-invasive diagnostic tests for AD remains, however, an unmet need. In the present proof-of-concept study we investigated tear fluid as a novel source of disease-specific protein and microRNA-based biomarkers for AD development using samples from patients with mild cognitive impairment (MCI) and AD. Tear protein content was evaluated via liquid chromatography-mass spectrometry and microRNA content was profiled using a genome-wide high-throughput PCR-based platform. These complementary approaches identified enrichment of specific proteins and microRNAs in tear fluid of AD patients. In particular, we identified elongation initiation factor 4E (eIF4E) as a unique protein present only in AD samples. Total microRNA abundance was found to be higher in tears from AD patients. Among individual microRNAs, microRNA-200b-5p was identified as a potential biomarker for AD with elevated levels present in AD tear fluid samples compared to controls. Our study suggests that tears may be a useful novel source of biomarkers for AD and that the identification and verification of biomarkers within tears may allow for the development of a non-invasive and cost-effective diagnostic test for AD.

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