Dataset Information

Modulation of Cytosolic Phospholipase A2 as a Potential Therapeutic Strategy for Alzheimer's Disease.

ABSTRACT:

Background

Alzheimer's disease (AD) is a neurodegenerative disorder lacking any curative treatment up to now. Indeed, actual medication given to the patients alleviates only symptoms. The cytosolic phospholipase A2 (cPLA₂-IVA) appears as a pivotal player situated at the center of pathological pathways leading to AD and its inhibition could be a promising therapeutic approach.

Objective

A cPLA₂-IVA inhibiting peptide was identified in the present work, aiming to develop an original therapeutic strategy.

Methods

We targeted the cPLA₂-IVA using the phage display technology. The hit peptide PLP25 was first validated in vitro (arachidonic acid dosage [AA], cPLA₂-IVA cellular translocation) before being tested in vivo. We evaluated spatial memory using the Barnes maze, amyloid deposits by MRI and immunohistochemistry (IHC), and other important biomarkers such as the cPLA₂-IVA itself, the NMDA receptor, AβPP and tau by IHC after i.v. injection in APP/PS1 mice.

Results

Showing a high affinity for the C2 domain of this enzyme, the peptide PLP25 exhibited an inhibitory effect on cPLA₂-IVA activity by blocking its binding to its substrate, resulting in a decreased release of AA. Coupled to a vector peptide (LRPep2) in order to optimize brain access, we showed an improvement of cognitive abilities of APP/PS1 mice, which also exhibited a decreased number of amyloid plaques, a restored expression of cPLA₂-IVA, and a favorable effect on NMDA receptor expression and tau protein phosphorylation.

Conclusions

cPLA₂-IVA inhibition through PLP25 peptide could be a promising therapeutic strategy for AD.

SUBMITTER: Andre S

PROVIDER: S-EPMC10789292 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Modulation of Cytosolic Phospholipase A2 as a Potential Therapeutic Strategy for Alzheimer's Disease.

André Séverine S Verteneuil Sébastien S Ris Laurence L Kahvecioglu Zehra-Cagla ZC Nonclercq Denis D De Winter Julien J Vander Elst Luce L Laurent Sophie S Muller Robert N RN Burtea Carmen C

Journal of Alzheimer's disease reports 20231229 1

<h4>Background</h4>Alzheimer's disease (AD) is a neurodegenerative disorder lacking any curative treatment up to now. Indeed, actual medication given to the patients alleviates only symptoms. The cytosolic phospholipase A2 (cPLA<sub>2</sub>-IVA) appears as a pivotal player situated at the center of pathological pathways leading to AD and its inhibition could be a promising therapeutic approach.<h4>Objective</h4>A cPLA<sub>2</sub>-IVA inhibiting peptide was identified in the present work, aiming ...[more]

PMID: 38225969

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Project description:ObjectiveTumour necrosis factor alpha (TNF-α) signalling plays a central role in the pathogenesis of various autoimmune diseases, particularly inflammatory arthritis. This study aimed to repurpose clinically approved drugs as potential inhibitors of TNF-α signalling in treatment of inflammatory arthritis.MethodsIn vitro and in vivo screening of an Food and Drug Administration (FDA)-approved drug library; in vitro and in vivo assays for examining the blockade of TNF actions by fexofenadine: assays for defining the anti-inflammatory activity of fexofenadine using TNF-α transgenic (TNF-tg) mice and collagen-induced arthritis in DBA/1 mice. Identification and characterisation of the binding of fexofenadine to cytosolic phospholipase A2 (cPLA2) using drug affinity responsive target stability assay, proteomics, cellular thermal shift assay, information field dynamics and molecular dynamics; various assays for examining fexofenadine inhibition of cPLA2 as well as the dependence of fexofenadine's anti-TNF activity on cPLA2.ResultsSerial screenings of a library composed of FDA-approved drugs led to the identification of fexofenadine as an inhibitor of TNF-α signalling. Fexofenadine potently inhibited TNF/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) signalling in vitro and in vivo, and ameliorated disease symptoms in inflammatory arthritis models. cPLA2 was isolated as a novel target of fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished fexofenadine's anti-TNF activity.ConclusionCollectively, these findings not only provide new insights into the understanding of fexofenadine action and underlying mechanisms but also provide new therapeutic interventions for various TNF-α and cPLA2-associated pathologies and conditions, particularly inflammatory rheumatic diseases.

Dataset Information

Modulation of Cytosolic Phospholipase A2 as a Potential Therapeutic Strategy for Alzheimer's Disease.

Background

Objective

Methods

Results

Conclusions

Publications

Modulation of Cytosolic Phospholipase A2 as a Potential Therapeutic Strategy for Alzheimer's Disease.

Similar Datasets

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