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

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 (cPLA ₂ -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 cPLA ₂ -IVA inhibiting peptide was identified in the present work, aiming to develop an original therapeutic strategy.
Methods: We targeted the cPLA ₂ -IVA using the phage display technology. The hit peptide PLP25 was first validated in vitro (arachidonic acid dosage [AA], cPLA ₂ -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 cPLA ₂ -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 cPLA ₂ -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 cPLA ₂ -IVA, and a favorable effect on NMDA receptor expression and tau protein phosphorylation.
Conclusions: cPLA ₂ -IVA inhibition through PLP25 peptide could be a promising therapeutic strategy for AD.
Competing Interests: The authors have no conflict of interest to report.
(© 2023 – The authors. Published by IOS Press.)