scholarly journals P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

2020 ◽  
Vol 21 (15) ◽  
pp. 5485
Author(s):  
Ursula A. Germann ◽  
John J. Alam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Therapeutic Target ◽  
Kinase Inhibitors ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Effects ◽  
P38α Kinase

Multifactorial pathologies, involving one or more aggregated protein(s) and neuroinflammation are common in major neurodegenerative diseases, such as Alzheimer’s disease and dementia with Lewy bodies. This complexity of multiple pathogenic drivers is one potential explanation for the lack of success or, at best, the partial therapeutic effects, respectively, with approaches that have targeted one specific driver, e.g., amyloid-beta, in Alzheimer’s disease. Since the endosome-associated protein Rab5 appears to be a convergence point for many, if not all the most prominent pathogenic drivers, it has emerged as a major therapeutic target for neurodegenerative disease. Further, since the alpha isoform of p38 mitogen-activated protein kinase (p38α) is a major regulator of Rab5 activity and its effectors, a biology that is distinct from the classical nuclear targets of p38 signaling, brain-penetrant selective p38α kinase inhibitors provide the opportunity for significant therapeutic advances in neurogenerative disease through normalizing dysregulated Rab5 activity. In this review, we provide a brief summary of the role of Rab5 in the cell and its association with neurodegenerative disease pathogenesis. We then discuss the connection between Rab5 and p38α and summarize the evidence that through modulating Rab5 activity there are therapeutic opportunities in neurodegenerative diseases for p38α kinase inhibitors.

scholarly journals Corticotropin releasing factor-binding protein (CRF-BP) as a potential new therapeutic target in Alzheimer’s disease and stress disorders

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Dorien Vandael ◽  
Natalia V. Gounko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Therapeutic Target ◽  
Life Stress ◽  
Binding Protein ◽  
Critical Role ◽  
Treatment Strategies ◽  
Corticotropin Releasing Factor ◽  
Stress Disorders

Abstract Alzheimer’s disease is the most common cause of dementia and one of the most complex human neurodegenerative diseases. Numerous studies have demonstrated a critical role of the environment in the pathogenesis and pathophysiology of the disease, where daily life stress plays an important role. A lot of epigenetic studies have led to the conclusion that chronic stress and stress-related disorders play an important part in the onset of neurodegenerative disorders, and an enormous amount of research yielded valuable discoveries but has so far not led to the development of effective treatment strategies for Alzheimer’s disease. Corticotropin-releasing factor (CRF) is one of the major hormones and at the same time a neuropeptide acting in stress response. Deregulation of protein levels of CRF is involved in the pathogenesis of Alzheimer’s disease, but little is known about the precise roles of CRF and its binding protein, CRF-BP, in neurodegenerative diseases. In this review, we summarize the key evidence for and against the involvement of stress-associated modulation of the CRF system in the pathogenesis of Alzheimer’s disease and discuss how recent findings could lead to new potential treatment possibilities in Alzheimer’s disease by using CRF-BP as a therapeutic target.

scholarly journals MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Yehong Du ◽  
Yexiang Du ◽  
Yun Zhang ◽  
Zhilin Huang ◽  
Min Fu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Amyloid Β ◽  
Gene Promoter ◽  
Long Term Potentiation ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase

AbstractMitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is an essential negative regulator of MAPKs by dephosphorylating MAPKs at both tyrosine and threonine residues. Dysregulation of the MAPK signaling pathway has been associated with Alzheimer’s disease (AD). However, the role of MKP-1 in AD pathogenesis remains elusive. Here, we report that MKP-1 levels were decreased in the brain tissues of patients with AD and an AD mouse model. The reduction in MKP-1 gene expression appeared to be a result of transcriptional inhibition via transcription factor specificity protein 1 (Sp1) cis-acting binding elements in the MKP-1 gene promoter. Amyloid-β (Aβ)-induced Sp1 activation decreased MKP-1 expression. However, upregulation of MKP-1 inhibited the expression of both Aβ precursor protein (APP) and β-site APP-cleaving enzyme 1 by inactivating the extracellular signal-regulated kinase 1/2 (ERK)/MAPK signaling pathway. Furthermore, upregulation of MKP-1 reduced Aβ production and plaque formation and improved hippocampal long-term potentiation (LTP) and cognitive deficits in APP/PS1 transgenic mice. Our results demonstrate that MKP-1 impairment facilitates the pathogenesis of AD, whereas upregulation of MKP-1 plays a neuroprotective role to reduce Alzheimer-related phenotypes. Thus, this study suggests that MKP-1 is a novel molecule for AD treatment.

scholarly journals Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

2018 ◽  
Vol 46 (4) ◽  
pp. 891-909 ◽  
Author(s):  
Ruby Macdonald ◽  
Katy Barnes ◽  
Christopher Hastings ◽  
Heather Mortiboys
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Therapeutic Target ◽  
Mitochondrial Dynamics ◽  
Central Mechanism ◽  
Phenotypic Screening ◽  
Mitochondrial Abnormalities

Mitochondrial abnormalities have been identified as a central mechanism in multiple neurodegenerative diseases and, therefore, the mitochondria have been explored as a therapeutic target. This review will focus on the evidence for mitochondrial abnormalities in the two most common neurodegenerative diseases, Parkinson's disease and Alzheimer's disease. In addition, we discuss the main strategies which have been explored in these diseases to target the mitochondria for therapeutic purposes, focusing on mitochondrially targeted antioxidants, peptides, modulators of mitochondrial dynamics and phenotypic screening outcomes.

scholarly journals Identification of conserved proteomic networks in neurodegenerative dementia

2019 ◽  
Author(s):  
Vivek Swarup ◽  
Timothy S. Chang ◽  
Duc M. Duong ◽  
Eric B. Dammer ◽  
James J. Lah ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Genetic Risk ◽  
Cell Interaction ◽  
Mapk Signaling ◽  
Postmortem Brain ◽  
List Type ◽  
Label Free ◽  
High Confidence

SummaryData-driven analyses of human brain across neurodegenerative diseases possess the potential for identifying disease-specific and shared biological processes. We integrated functional genomics data from postmortem brain, including label-free quantitative proteomics and RNA-seq based transcriptomics in an unprecedented dataset of over 1000 individuals across 5 cohorts representing Alzheimer’s disease (AD), asymptomatic AD, Progressive Supranuclear Palsy (PSP), and control patients, as a core analysis of the Accelerating Medicines Project – Alzheimer’s Disease (AMP-AD) consortium. We identified conserved, high confidence proteomic changes during the progression of dementias that were absent in other neurodegenerative disorders. We defined early changes in asymptomatic AD cases that included microglial, astrocyte, and immune response modules and later changes related to synaptic processes and mitochondria, many, but not all of which were conserved at the transcriptomic level. This included a novel module C3, which is enriched in MAPK signaling, and only identified in proteomic networks. To understand the relationship of core molecular processes with causal genetic drivers, we identified glial, immune, and cell-cell interaction processes in modules C8 and C10, which were robustly preserved in multiple independent data sets, up-regulated early in the disease course, and enriched in AD common genetic risk. In contrast to AD, PSP genetic risk was enriched in module C1, which represented synaptic processes, clearly demonstrating that despite shared pathology such as synaptic loss and glial inflammatory changes, AD and PSP have distinct causal drivers. These conserved, high confidence proteomic changes enriched in genetic risk represent new targets for drug discovery.HighlightsWe distinguish robust early and late proteomic changes in AD in multiple cohorts.We identify changes in dementias that are not preserved in other neurodegenerative diseases.AD genetic risk is enriched in early up-regulated glial-immune modules and PSP in synaptic modules.Almost half of the variance in protein expression reflects gene expression, but an equal fraction is post-transcriptional or -translational.

scholarly journals SkQ1 Suppresses the p38 MAPK Signaling Pathway Involved in Alzheimer’s Disease-Like Pathology in OXYS Rats

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 676
Author(s):  
Natalia A. Muraleva ◽  
Natalia A. Stefanova ◽  
Nataliya G. Kolosova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Oxys Rats ◽  
Mitogen Activated Protein Kinase ◽  
Immunofluorescent Staining ◽  
Αb Crystallin

Alzheimer’s disease (AD) is the most common type of dementia and is currently incurable, and mitogen-activated protein kinase (MAPK) p38 is implicated in the pathogenesis of AD. p38 MAPK inhibition is considered a promising strategy against AD, but there are no safe inhibitors capable of penetrating the blood–brain barrier. Earlier, we have shown that mitochondria-targeted antioxidant plastoquinonyl-decyltriphenylphosphonium (SkQ1) at nanomolar concentrations can prevent, slow down, or partially alleviate AD-like pathology in accelerated-senescence OXYS rats. Here we confirmed that dietary supplementation with SkQ1 during active progression of AD-like pathology in OXYS rats (aged 12–18 months) suppresses AD-like pathology progression, and for the first time, we showed that its effects are associated with suppression of p38 MAPK signaling pathway (MAPKsp) activity. Transcriptome analysis, western blotting, and immunofluorescent staining revealed that SkQ1 suppresses p38 MAPKsp activity in the hippocampus at the level of expression of genes involved in the p38 MAPKsp and reduces the phosphorylation of intermediate kinases (p38 MAPK and MK2) and a downstream protein (αB-crystallin). Thus, the anti-AD effects of SkQ1 are associated with improvement in the functioning of relevant signaling pathways and intracellular processes, thus making it a promising therapeutic agent for human AD.

scholarly journals The Application of Seaweed Polysaccharides and Their Derived Products with Potential for the Treatment of Alzheimer’s Disease

Marine Drugs ◽  
2021 ◽  
Vol 19 (2) ◽  
pp. 89
Author(s):  
Sarah Bauer ◽  
Weihua Jin ◽  
Fuming Zhang ◽  
Robert J. Linhardt
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Research Area ◽  
Important Research ◽  
Disease Treatment ◽  
Number Of Patients ◽  
Important Research Area

Neurodegenerative diseases are among the most widespread diseases affecting humans, and the number of patients is only rising. Seaweed polysaccharide extracts show significant neuroprotective and reparative activities. Seaweed polysaccharides might provide the next big breakthrough in neurodegenerative disease treatment. This paper reviews the applications of seaweed polysaccharides as potential treatments of neurodegenerative diseases. The particular focus is on fucoidan, ulvan, and their derivatives as potential agents to treat Alzheimer’s disease. This review provides a critical update on the progress in this important research area.

scholarly journals Possible Role of the Transglutaminases in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Antonio Martin ◽  
Giulia De Vivo ◽  
Vittorio Gentile
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Therapeutic Effects ◽  
Polyglutamine Diseases ◽  
Post Translational Modification ◽  
Transglutaminase Activity

Transglutaminases are ubiquitous enzymes which catalyze posttranslational modifications of proteins. Recently, transglutaminase-catalyzed post-translational modification of proteins has been shown to be involved in the molecular mechanisms responsible for human diseases. Transglutaminase activity has been hypothesized to be involved also in the pathogenetic mechanisms responsible for several human neurodegenerative diseases. Alzheimer's disease and other neurodegenerative diseases, such as Parkinson's disease, supranuclear palsy, Huntington's disease, and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This paper focuses on the possible molecular mechanisms by which transglutaminase activity could be involved in the pathogenesis of Alzheimer's disease and other neurodegenerative diseases, and on the possible therapeutic effects of selective transglutaminase inhibitors for the cure of patients with diseases characterized by aberrant transglutaminase activity.

scholarly journals The inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration

2020 ◽  
Vol 117 (46) ◽  
pp. 29133-29143
Author(s):  
Amanda K. Engstrom ◽  
Alicia C. Walker ◽  
Rohitha A. Moudgal ◽  
Dexter A. Myrick ◽  
Stephanie M. Kyle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Neurodegenerative Diseases ◽  
Therapeutic Target ◽  
Cortical Neurons ◽  
Histone Demethylase ◽  
Direct Mechanism ◽  
Promising Therapeutic Target

Tauopathies are a class of neurodegenerative diseases associated with pathological tau. Despite many advances in our understanding of these diseases, the direct mechanism through which tau contributes to neurodegeneration remains poorly understood. Previously, our laboratory implicated the histone demethylase LSD1 in tau-induced neurodegeneration by showing that LSD1 localizes to pathological tau aggregates in Alzheimer's disease cases, and that it is continuously required for the survival of hippocampal and cortical neurons in mice. Here, we utilize the P301S tauopathy mouse model to demonstrate that pathological tau can exclude LSD1 from the nucleus in neurons. In addition, we show that reducing LSD1 in these mice is sufficient to highly exacerbate tau-mediated neurodegeneration and tau-induced gene expression changes. Finally, we find that overexpressing LSD1 in the hippocampus of tauopathy mice, even after pathology has formed, is sufficient to significantly delay neurodegeneration and counteract tau-induced expression changes. These results suggest that inhibiting LSD1 via sequestration contributes to tau-mediated neurodegeneration. Thus, LSD1 is a promising therapeutic target for tauopathies such as Alzheimer's disease.

scholarly journals Significance of Hypouricaemia in the Development of Neurodegenerative Diseases

2021 ◽  
Vol 75 (2) ◽  
pp. 92-98
Author(s):  
Maximiliane Trapp ◽  
Anna Mihailova ◽  
Natalija Kakurina ◽  
Modra Murovska
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Uric Acid ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Vascular Dementia ◽  
Neuroprotective Effect ◽  
Significant Difference ◽  
Potential Risks

Abstract Hypouricaemia has received relatively little attention in the literature. As a result, there is less awareness or understanding of the potential risks of low uric acid levels. Emerging research indicates that normal uric acid levels may have an antioxidative and neuroprotective effect. This study aims to investigate possible associations between hypouricaemia and neurodegenerative disease. Data was collected from seventy-seven outpatients and inpatients who underwent routine uric acid testing, who were then stratified into patients with and without neurodegenerative disease. Patients with renal pathologies and patients using uric acid altering medications were excluded from the study. There was a significant difference in the prevalence of Alzheimer’s disease between hypouricemic and normouricemic patients (p = 0.001), however there was no difference in the prevalence of vascular dementia (p = 0.45). This study provides evidence that hypouricaemia has potential effects on health, specifically on the rate of neurodegenerative diseases such as Alzheimer’s disease and gives weight to the potential neuroprotective role of uric acid.

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