PPKC ε mediated metalloproteinase 2 and 9 levels upon ibuprofen and lipoic acid coniugate (codrug 1) treatment in an Alzheimer disease rat brain model

Abstract

Alzheimer’s Disease (AD) begins with loss of recent memory and is associated to pathological and histological hallmarks such as β amyloid plaques, neural tangles (NFT), cholinergic deficit, extensive neuronal loss and synaptic changes in the cerebral cortex and hippocampus. The amyloid cascade hypothesis implies the activity of β, γ secretases which mediate the cleavage of Amyloid Precursor Protein (APP), the formation of amyloidogenic Aβ fragment (1-42), which compacts into amyloid plaques, while the cleavage by ? secretase of APP, within the Aβ segment forms sAPP and prevents the formation of Aβ (Zetterberg et al. 2010 Exp Gerontol 45, 23-29). Among the proteases which have Aβ-degrading activity, Metalloproteinase (MMP) 2, disclosing β secretase-like activity, is included, while MMP9 seems to contribute to neuronal death (Yan et al. 2006 J Biol Chem 281, 24566-74). In addition, intracellular signalling protein Protein Kinase C (PKC) can control ? secretase, preventing the formation of β amyloid, and prolonging the life span of AD (de Barry et al. 2010 Exp Gerontol 45, 64-69). A lipophilic molecular combination (codrug 1), obtained by joining an antioxidant molecule, lipoic acid, with an anti-inflammatory compound, ibuprofen (IBU) has been synthetized in our lab and administered in a chronic treatment during intracerebroventricular infusion of Aβ (1-40) peptide in rat brains as a model of AD (Sozio et al. 2010 Arch Pharm 343,133-42). Here we show the effects exerted by codrug 1 on PKC e-mediated MMP2 and MMP9 levels regulation in Aβ (1-40) infused rat cerebral cortex. Interestingly codrug 1, lowering Metalloproteinases expression via PKC e down-modulation, seems to control Alzheimer’s disease induced cerebral amyloid deposits, neuronal death and, lastly, behavioural deterioration. Moreover the cognitive test evidences that codrug 1 treatment decreases the number of reference memory errors and the time spent to perform the test suggesting this compound as an useful therapeutical tool against AD.