Ibuprofen and lipoic acid codrug 1 control Alzheimer's disease progression by down-regulating protein kinase C epsilon-mediated metalloproteinase 2 and 9 levels in beta-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 Abeta fragment (1-42), which compacts into amyloid plaques, while the cleavage by alpha secretase of APP, within the Abeta segment (non-amyloidogenic processing) forms sAPP and prevents the formation of Abeta. Among the proteases which have Abeta-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 ± 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 µ-mediated MMP2 and MMP9 levels regulation in Abeta (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