P3-208 Role of caspase family proteases in amyloid beta-induced neuronal death

Alzheimer's disease is a neurodegenerative condition characterized by an accumulation of toxic amyloid beta- (A-)peptides in the brain causing progressive neuronal death. A-peptides are produced by aspartyl proteinase-mediated cleavage of the larger amyloid precursor protein (APP). In contrast to this detrimental “amyloidogenic” form of proteolysis, a range of zinc metalloproteinases can process APP via an alternative “nonamyloidogenic” pathway in which the protein is cleaved within its A region thereby precluding the formation of intact A-peptides. In addition, other members of the zinc metalloproteinase family can degrade preformed A-peptides. As such, the zinc metalloproteinases, collectively, are key to downregulating A generation and enhancing its degradation. It is the role of zinc metalloproteinases in this “positive side of proteolysis in Alzheimer's disease” that is discussed in the current paper.

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Protective Role of Glutathione in the Hippocampus after Brain Ischemia

International Journal of Molecular Sciences ◽

10.3390/ijms22157765 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7765

Author(s):

Youichirou Higashi ◽

Takaaki Aratake ◽

Takahiro Shimizu ◽

Shogo Shimizu ◽

Motoaki Saito

Keyword(s):

Oxidative Stress ◽

Neuronal Death ◽

Excitatory Amino Acid ◽

Ischemia Reperfusion ◽

Thiol Group ◽

Protective Role ◽

Key Factor ◽

Rate Limiting ◽

Cysteine Uptake

Stroke is a major cause of death worldwide, leading to serious disability. Post-ischemic injury, especially in the cerebral ischemia-prone hippocampus, is a serious problem, as it contributes to vascular dementia. Many studies have shown that in the hippocampus, ischemia/reperfusion induces neuronal death through oxidative stress and neuronal zinc (Zn2+) dyshomeostasis. Glutathione (GSH) plays an important role in protecting neurons against oxidative stress as a major intracellular antioxidant. In addition, the thiol group of GSH can function as a principal Zn2+ chelator for the maintenance of Zn2+ homeostasis in neurons. These lines of evidence suggest that neuronal GSH levels could be a key factor in post-stroke neuronal survival. In neurons, excitatory amino acid carrier 1 (EAAC1) is involved in the influx of cysteine, and intracellular cysteine is the rate-limiting substrate for the synthesis of GSH. Recently, several studies have indicated that cysteine uptake through EAAC1 suppresses ischemia-induced neuronal death via the promotion of hippocampal GSH synthesis in ischemic animal models. In this article, we aimed to review and describe the role of GSH in hippocampal neuroprotection after ischemia/reperfusion, focusing on EAAC1.

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Caspase-14—From Biomolecular Basics to Clinical Approach. A Review of Available Data

International Journal of Molecular Sciences ◽

10.3390/ijms22115575 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5575

Author(s):

Agnieszka Markiewicz ◽

Dawid Sigorski ◽

Mateusz Markiewicz ◽

Agnieszka Owczarczyk-Saczonek ◽

Waldemar Placek

Keyword(s):

Cell Death ◽

Physiological Role ◽

Skin Barrier ◽

Clinical Aspects ◽

Clinical Approach ◽

Search Term ◽

Caspase Family ◽

Skin Conditions ◽

Theoretical Science

Caspase-14 is a unique member of the caspase family—a family of molecules participating in apoptosis. However, it does not affect this process but regulates another form of programmed cell death—cornification, which is characteristic of the epidermis. Therefore, it plays a crucial role in the formation of the skin barrier. The cell death cycle has been a subject of interest for researchers for decades, so a lot of research has been done to expand the understanding of caspase-14, its role in cell homeostasis and processes affecting its expression and activation. Conversely, it is also an interesting target for clinical researchers searching for its role in the physiology of healthy individuals and its pathophysiology in particular diseases. A summary was done in 2008 by Denecker et al., concentrating mostly on the biotechnological aspects of the molecule and its physiological role. However, a lot of new data have been reported, and some more practical and clinical research has been conducted since then. The majority of studies tackled the issue of clinical data presenting the role of caspase in the etiopathology of many diseases such as retinal dysfunctions, multiple malignancies, and skin conditions. This review summarizes the available knowledge on the molecular and, more interestingly, the clinical aspects of caspase-14. It also presents how theoretical science may pave the way for medical research. Methods: The authors analyzed publications available on PubMed until 21 March 2021, using the search term “caspase 14”.

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Role of amyloid $beta;-protein in Alzheimer's disease

The Lancet ◽

10.1016/0140-6736(92)92725-u ◽

1992 ◽

Vol 340 (8823) ◽

pp. 850-851 ◽

Cited By ~ 1

Author(s):

A BARKER

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Amyloid Beta Protein

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Functional outcome after intracerebral haemorrhage – a review of the potential role of antiapoptotic agents

Reviews in the Neurosciences ◽

10.1515/revneuro-2015-0046 ◽

2016 ◽

Vol 27 (3) ◽

pp. 317-327 ◽

Cited By ~ 8

Author(s):

Abubakar Tijjani Salihu ◽

Sangu Muthuraju ◽

Zamzuri Idris ◽

Abdul Rahman Izaini Ghani ◽

Jafri Malin Abdullah

Keyword(s):

Functional Outcome ◽

Intracerebral Haemorrhage ◽

Neuronal Death ◽

Potential Role ◽

Management Strategies ◽

Experimental Studies ◽

Neuronal Loss ◽

Multimodality Treatment ◽

Mortality And Morbidity

AbstractIntracerebral haemorrhage (ICH) is the second most common form of stroke and is associated with greater mortality and morbidity compared with ischaemic stroke. The current ICH management strategies, which mainly target primary injury mechanisms, have not been shown to improve patient’s functional outcome. Consequently, multimodality treatment approaches that will focus on both primary and secondary pathophysiology have been suggested. During the last decade, a proliferation of experimental studies has demonstrated the role of apoptosis in secondary neuronal loss at the periphery of the clot after ICH. Subsequently, the value of certain antiapoptotic agents in reducing neuronal death and improving functional outcome following ICH was evaluated in animal models. Preliminary evidence from those studies strongly supports the potential role of antiapoptotic agents in reducing neuronal death and improving functional outcome after intracerebral haemorrhage. Expectedly, the ongoing and subsequent clinical trials will substantiate these findings and provide clear information on the most potent and safe antiapoptotic agents, their appropriate dosage, and temporal window of action, thereby making them suitable for the multimodality treatment approach.

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Emerging role of amyloid beta in stress response: Implication for depression and diabetes

European Journal of Pharmacology ◽

10.1016/j.ejphar.2017.08.031 ◽

2017 ◽

Vol 817 ◽

pp. 22-29 ◽

Cited By ~ 21

Author(s):

Maria Grazia Morgese ◽

Stefania Schiavone ◽

Luigia Trabace

Keyword(s):

Stress Response ◽

Amyloid Beta

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Mechanisms of neuronal death in disease: defining the models and the players

Biochemical Journal ◽

10.1042/bj20081118 ◽

2008 ◽

Vol 415 (2) ◽

pp. 165-182 ◽

Cited By ~ 61

Author(s):

Elena M. Ribe ◽

Esther Serrano-Saiz ◽

Nsikan Akpan ◽

Carol M. Troy

Keyword(s):

Neurodegenerative Diseases ◽

Neuronal Death ◽

Neurological Disease ◽

Neurodegenerative Disorder ◽

Cellular Level ◽

Therapeutic Interventions ◽

Common Cause ◽

Life And Death ◽

Caspase Family ◽

Common Neurodegenerative Disorder

Dysregulation of life and death at the cellular level leads to a variety of diseases. In the nervous system, aberrant neuronal death is an outstanding feature of neurodegenerative diseases. Since the discovery of the caspase family of proteases, much effort has been made to determine how caspases function in disease, including neurodegenerative diseases. Although many papers have been published examining caspases in neuronal death and disease, the pathways have not been fully clarified. In the present review, we examine the potential players in the death pathways, the current tools for examining these players and the models for studying neurological disease. Alzheimer's disease, the most common neurodegenerative disorder, and cerebral ischaemia, the most common cause of neurological death, are used to illustrate our current understanding of death signalling in neurodegenerative diseases. A better understanding of the neuronal death pathways would provide targets for the development of therapeutic interventions for these diseases.

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Inflammation and JNK's Role in Niacin-GPR109A Diminished Flushed Effect in Microglial and Neuronal Cells With Relevance to Schizophrenia

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.771144 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sabrina H. Ansarey

Keyword(s):

Inflammatory Mediators ◽

Neuronal Death ◽

Microglial Activation ◽

Negative Symptoms ◽

Genome Wide Association Study ◽

Genetic Mutation ◽

Genome Wide ◽

Ultra High Risk ◽

Altered Proteins

Schizophrenia is a neuropsychiatric illness with no single definitive aetiology, making its treatment difficult. Antipsychotics are not fully effective because they treat psychosis rather than the cognitive or negative symptoms. Antipsychotics fail to alleviate symptoms when patients enter the chronic stage of illness. Topical application of niacin showed diminished skin flush in the majority of patients with schizophrenia compared to the general population who showed flushing. The niacin skin flush test is useful for identifying patients with schizophrenia at their ultra-high-risk stage, and understanding this pathology may introduce an effective treatment. This review aims to understand the pathology behind the diminished skin flush response, while linking it back to neurons and microglia. First, it suggests that there are altered proteins in the GPR109A-COX-prostaglandin pathway, inflammatory imbalance, and kinase signalling pathway, c-Jun N-terminal kinase (JNK), which are associated with diminished flush. Second, genes from the GPR109A-COX-prostaglandin pathway were matched against the 128-loci genome wide association study (GWAS) for schizophrenia using GeneCards, suggesting that G-coupled receptor-109A (GPR109A) may have a genetic mutation, resulting in diminished flush. This review also suggests that there may be increased pro-inflammatory mediators in the GPR109A-COX-prostaglandin pathway, which contributes to the diminished flush pathology. Increased levels of pro-inflammatory markers may induce microglial-activated neuronal death. Lastly, this review explores the role of JNK on pro-inflammatory mediators, proteins in the GPR109A-COX-prostaglandin pathway, microglial activation, and neuronal death. Inhibiting JNK may reverse the changes observed in the diminished flush response, which might make it a good therapeutic target.

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