Evaluation of the Role of JNK1 in the Hippocampus in an Experimental Model of Familial Alzheimer's Disease

c-Jun N-terminal kinases (JNKs), which belong to a mitogen-activated protein kinase (MAPK) family, are involved in the regulation of several physiological functions in mammals and act as mediators of apoptosis, obesity, and memory storage in the brain, including the processes of neuronal de- and regeneration. JNK subfamily is encoded by three separate but related genes: jnk1, jnk2, and jnk3, giving rise to at least ten distinct splice variants of the JNK proteins. JNK3 is thought to be a major contributor to neurodegeneration in mammalian brain. The role of JNK1 in the pathological processes affecting cognitive function, especially in diseases such as Alzheimer's disease (AD), is less clear. In order to evaluate the effects of JNK1 deficiency in an experimental model of familial Alzheimer's disease, double transgenic APPswe/PS1dE9 mice were crossed with the JNK1 heterozygous deficient animals (jnk1+/-). As expected, a similar to 50 % reduction in JNK1 protein levels was observed in the hippocampi of 9-month-old APPswe/PS1dE9/jnk1+/- mice, compared with the APPswe/PS1dE9 group. JNK1 deficiency resulted in reduced BACE1 expression, suggesting alterations in amyloidogenic pathway. However, no significant inter-group differences in the total number of beta-amyloid plaques were observed in the hippocampal region. In addition, protein levels of PPAR gamma coactivator-1 alpha (PGC-1 alpha), a molecule involved in mitochondrial biogenesis and energy homeostasis, were decreased in 9-month-old APPswe/PS1dE9 mice but not in APPswe/PS1dE9/jnk1+/- animals. Furthermore, JNK1 deficiency did not have an effect on pro-inflammatory marker expression in the hippocampus. Heterozygous deficiency of JNK1 results in the decrease of BACE1 protein levels, which is not accompanied by the reduction in the total number of beta-amyloid plaques in the hippocampi of APPswe/PS1dE9 mice. Moreover, PGC-1 alpha expression is restored in APPswe/PS1dE9/jnk1+/- animals, which indicates a possible role of JNK1 in brain mitochondrial regulation. Nevertheless, our results suggest that partial inhibition of JNK1 is not sufficient to prevent the neuropathological processes in this model. It may be necessary to inhibit both the JNK1 and JNK3 simultaneously, especially as previous studies suggest that JNK3 contributes to AD neuropathology.