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

Alzheimer's disease (AD) commonly begins with loss of recent memory and is associated to pathological and histological hallmarks such as beta 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 beta, gamma secretases which mediate the cleavage of APP (Amyloid Precursor Protein), the formation of amyloidogenic A beta fragment (1-42), which compacts into amyloid plaques, while the cleavage by alpha secretase of APP, within the A beta segment (non-amyloidogenic processing) forms sAPP and prevents the formation of A beta. Among the proteases which have A beta-degrading activity, Metalloproteinase (MMP) 2, disclosing beta 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 alpha secretase or indirectly through regulation of ERK1/2, preventing the formation of beta amyloid, created by beta and gamma secretase, and prolonging the life span of Alzheimer's disease mutant mice, here we show the effects exerted by new codrug 1 on PKC epsilon-mediated MMP2 and MMP9 levels regulation in A beta (1-40) infused rat cerebral cortex. Interestingly codrug 1, lowering metalloproteinases expression via PKC epsilon down-modulation, seems to control Alzheimer's disease induced cerebral amyloid deposits, neuronal death and, lastly, behavioral deterioration. (C) 2011 Elsevier B.V. All rights reserved.