Research Report Ibuprofen and lipoic acid codrug 1 control Alzheimer's disease progression by down-regulating protein kinase C ε-mediated metalloproteinase 2 and 9 levels in β-amyloid infused Alzheimer's disease rat model S. Zara a , M. Rapino c , P. Sozio a , A. Di Stefano a , C. Nasuti d , A. Cataldi b, ⁎ a Dipartimento di Scienze del Farmaco, Università G. d'Annunzio, Chieti-Pescara, Italy b Dipartimento di Medicina e Scienze dell' Invecchiamento, Università G. d'Annunzio, Chieti-Pescara, Italy c Istituto di Genetica Molecolare del CNR, Unità di Chieti, Italy d Dipartimento di Medicina Sperimentale e Sanità Pubblica, Università di Camerino, Camerino, Italy ARTICLE INFO ABSTRACT Article history: Accepted 10 July 2011 Available online 20 July 2011 Alzheimer's disease (AD) commonly 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 APP (Amyloid Precursor Protein), the formation of amyloidogenic Aβ fragment (1–42), which compacts into amyloid plaques, while the cleavage by α secretase of APP, within the Aβ segment (non-amyloidogenic processing) forms sAPP and prevents the formation of Aβ. 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. In addition, since intracellular signaling protein kinase C (PKC) can control either directly α secretase or indirectly through regulation of ERK1/2, preventing the formation of β amyloid, created by β and γ secretase, and prolonging the life span of Alzheimer's disease mutant mice, here we show the effects exerted by new codrug 1 on PKC ε-mediated MMP2 and MMP9 levels regulation in Aβ (1–40) infused rat cerebral cortex. Interestingly codrug 1, lowering metalloproteinases expression via PKC ε down-modulation, seems to control Alzheimer's disease induced cerebral amyloid deposits, neuronal death and, lastly, behavioral deterioration. © 2011 Elsevier B.V. All rights reserved. Keywords: Ibuprofen Lipoic acid Codrug 1 Alzheimer's disease PKCs Metalloproteinases 1. Introduction Alzheimer's disease (AD) is characterized not only by memory loss, unusual behavior, personality changes and declining in thinking activity but also by histological and molecular hall- marks, such as β amyloid plaques, intraneural tangles (NFT), cholinergic deficit, extensive neuronal loss and synaptic changes in the cerebral cortex and hippocampus, which can BRAIN RESEARCH 1412 (2011) 79 – 87 ⁎ Corresponding author at: Dipartimento di Medicina e Scienze dell'Invecchiamento, Università G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy. Fax: +39 0871 3554568. E-mail address: cataldi@unich.it (A. Cataldi). 0006-8993/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2011.07.022 available at www.sciencedirect.com www.elsevier.com/locate/brainres