The major goal of this study was to investigate the potential disease-modifying effects of SP600125, a small molecule JNK-specific inhibitor, in middle-aged APPswe/PS1dE9 mice. To more closely mimic the clinical setting the authors used 9-month-old APPswe/PS1dE9 mice exhibiting a subset of behavioral and pathological features of AD. Compared with vehicle-treated APPswe/PS1dE9 mice, chronic treatment of SP600125 for 12 weeks potently inhibited JNK activation, which resulted in a marked improvement of behavioral measures of cognitive deficits and a dramatic reduction in amyloid plaque burden, beta-amyloid production, tau hyperphosphorylation, inflammatory responses, and synaptic loss in these transgenic animals. In particular, data showed that SP600125 treatment strongly promoted non-amyloidogenic amyloid precursor protein (APP) processing and inhibited amyloidogenic APP processing via regulating APP-cleavage secretase expression (ie, ADAM10, BACE1, and PS1) in APPswe/PS1dE9 mice. Collectively, these findings demonstrate that specific inhibition of JNK activation by SP600125 treatment is powerfully effective in improving cognitive deficits and reducing multiple neuropathologies associated with AD, suggesting the potential of the specific inhibition of JNK activation by SP600125 treatment as a disease-modifying therapy for AD.