[en] Alzheimer's disease (AD) treatment is a challenge up to now, no new drug being approved by the FDA since 1993 [1], while the current therapies are only symptomatic. In this context, a phospholipase A2 (PLA2)-targeted peptide has been developed by our group aimed to reversibly and specifically modulate this enzyme involved in AD-associated signaling pathway dysregulation [2]. The existing PLA2 inhibitors show protection against apoptosis by amyloid beta (Aβ) [3] but are irreversible.
Our PLA2-targeted peptide (PLP25) was coupled to a peptide able to cross the blood-brain barrier (LRP2) in order to improve its brain availability and this complex (PLP25-LRP2) was tested in vitro and in vivo. PLP25-LRP2 reduces arachidonic acid (AA) release from PLA2-stimulated cells and blocks PLA2 translocation to cell membranes. This inhibition was indirectly propagated to related enzymes such as cyclooxygenases and lipoxygenases due to lower levels of AA. Filopodial dynamics and actin cytoskeleton reorganization were also modulated by PLP25-LRP2, phenomena associated to neuronal excitotoxicity. In vivo, PLP25-LRP2 seems to improve spatial memory of AD mouse model in the Barnes maze as compared to a non-specific peptide (NSP). Interestingly, treated mice exhibit a lower number of amyloid plaques, shown by molecular magnetic resonance imaging and immunohistochemistry, present a cellular localization of phosphorylated tau comparable to healthy mice, and expression levels of PLA2 and NMDA receptors restored to control levels.
Taken together, our results reveal the potential of our complex to be an original therapeutic strategy in AD.
1. Cummings JL et al. Alzheimers Res Ther. 2014;6: 37.
2. Schaeffer EL et al. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34: 1381-1389.
3. Farooqui AA et al. Pharmacol Rev. 2006;58: 591-620.
Research center :
CMMI - Centre de Recherche en Microscopie et Imagerie Médicale
