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 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.

► We used β-amyloid infused Alzheimer's disease rat model treated with codrug 1.
► codrug 1 regulates MMP2 and MMP9 levels.
► MMP2 and MMP9 regulation depends on PKC ε activation.
► codrug 1 regulates amyloid deposits, astrocytes death and behavioral deterioration.