Inhibition of c-Jun kinase provides neuroprotection in a model of Alzheimer's disease

The c-Jun N-terminal kinase (INK) pathway potentially links together the three major pathological hallmarks of Alzheimer's disease (AD): development of amyloid plaques, neurofibrillary tangles, and brain atrophy. As activation of the JNK pathway has been observed in amyloid models of AD in association with pen-plaque regions and neuritic dystrophy, as we confirm here for Tg2576/PSM146L transgenic mice, we directly tested whether JNK inhibition could provide neuroprotection in a novel brain slice model for amyloid precursor protein (APP)-induced neurodegeneration. We found that APP/amyloid beta (A beta)-induced neurodegeneration is blocked by both small molecule and peptide inhibitors of INK, and provide evidence that this neuroprotection occurs downstream of APP/A beta, production and processing. Our findings demonstrate that A beta can induce neurodegeneration, at least in part, through the INK pathway and suggest that inhibition of JNK may be of therapeutic utility in the treatment of AD. (C) 2010 Elsevier Inc. All rights reserved.