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2017-04-10 - Colloque/Présentation - poster - Anglais - 1 page(s)

Andre Séverine , Daldal Fatima, Delcroix Marie, Muller Robert , Vander Elst Luce , Laurent Sophie , Burtea Carmen , "Towards the therapy of Alzheimer’s disease via the inhibition of a phospholipase A2 isoform using peptides able to cross the blood-brain barrier" in BNA 2017 : festival of neuroscience, Birmingham, Angleterre, 2017

  • Codes CREF : Histologie (DI3212), Sciences biomédicales (DI3200), Biochimie pharmaceutique (DI3491), Biologie moléculaire (DI3111), Neuropathologie (DI332C), Biologie cellulaire (DI311D)
  • Unités de recherche UMONS : Chimie générale, organique et biomédicale (M108)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé), Institut des Biosciences (Biosciences)
  • Centres UMONS : Centre de Recherche en Microscopie et Imagerie Médicale (CMMI)

Abstract(s) :

(Anglais) Alzheimer’s disease (AD) is one of the main causes of dementia and its treatment is a real challenge. Phospholipase A2 (PLA2) signaling pathway was recently revealed to be involved in this pathology; its inhibition has already been shown to protect neurons against apoptosis induced by amyloid beta (Aβ). Aiming to preclude the neurodegenerative effects of PLA2 by limiting its activation, we have identified a PLA2-targeted peptide (PL-P25) by phage display. PL-P25 is able to prevent the PLA2 binding to cell membrane phospholipids and restores its activity in the range of controls. In human astrocytes (1321N1) and mouse neurons (N18) induced by H2O2 and glutamate respectively, known as PLA2 activators, a lower release of arachidonic acid levels was observed following the incubation with PL-P25. Furthermore, the treatment of brain diseases is complicated by the presence of the blood-brain barrier (BBB), protecting against xenobiotics and limiting the access of most molecules, including potential therapeutic agents. Non-invasive crossing strategies are thus indispensable to accede to the central nervous system (CNS) without BBB disruption. Because of its involvement in LDL transcytosis, LDL receptor (LDLR) turns out to be an attractive shuttling strategy for drug delivery. Following the LDLR-targeted phage display, the peptide LR-P2 was identified. This one colocalizes with LDLR on mouse brain slices and human brain endothelial cells (ACBRI376) and is endocytosed via a caveolae-mediated non-degradation pathway, whereas the lysosome degradation is bypassed. Recently, LR-P2 was covalently coupled to Ultrasmall Superparamagnetic Particles of Iron Oxide (USPIO-LRP2) and injected to healthy NMRI mice to evaluate the BBB crossing by Magnetic Resonance Imaging (MRI) and histology. USPIO-LRP2 was found within brain parenchyma, around the 3rd ventricle and brain capillaries, supporting the potential of LR-P2 to operate as a delivery agent of various pharmaceutical moieties, including our therapeutic peptide described above.