Targeting JNK for the diagnosis and treatment of Alzheimer's disease

Resumen

Alzheimer's disease (AD) affects over half million people in Spain and it is estimated that there are two million people directly related to the disease. Although AD etiology is still unknown, it seems is to be associated to neuronal apoptosis and synaptic terminals loss, resulting in neuroinflammation and neurodegeneration. In this context, different studies have shown the MAPK pathways involvement, such as JNK, in neuronal death and neuroinflammation. Evidence indicates that JNK cascade is activated in several experimental models of AD and its over-activation is related to AD pathology, such as maturation of neurofibrillary tangles and plaque formation senile. Last years, JNK inhibitors, omega 3 fatty acids (ù-3 PUFAs) among them, seem to have a potential development in clinical trials for different indications. Several studies and clinical research have suggested beneficial effects of marine omega 3 (ù-3 PUFAs) on neurodegenerative diseases, specifically EA. The ù-3 PUFAs therapeutic actions seem to be related to the resolution of neuroinflammation characteristic of AD. Although the beneficial effects of ù-3 PUFAs have been demonstrated in experimental models, the therapeutic effect in clinical trials is controversial. Therefore, it is suggested to study JNK pathway as therapeutic target or as complementary strategy to reduce pathological processes of AD. In the present project, it has been demonstrated the clear relationship between Aâ and JNK, highlighting the direct role of JNK in the pathology of AD. Our study has shown a specific and significant increase of activated JNK (pJNK) and Aâ levels of AD with a positive correlation between both levels, which has not been observed in any other dementia. Furthermore, the co-localization of JNK and Aâ in both murine models and AD patients reinforced this hypothesis. In addition, the causal relationship between Aâ and pJNK is also demonstrated, where Aâ induces JNK activation. Finally, pJNK is suggested as a biological marker of AD in cerebrospinal fluid. In order to study JNK inhibition as a therapeutic strategy for AD, three derivatives of ù-3 PUFAs (EPA, DHA and MaR1) were administered in a sporadic model of AD: SAMP8 mouse. As expected, SAMP8 mice showed cognitive deficit in two behavioural tests (Novel Object Recognition Test and Morris Water Maze) and only DHA treatment was able to counteract this cognitive deterioration. Based on these evidences, an attempt was made to elucidate the mechanism of action of these compounds, observing that there is a significant and negative correlation between pJNK levels and mice cognitive state. Therefore, DHA is able to reverse the increase in the levels of JNK in the SAMP8 mice compared to controls and this fact coincides with a cognitive improvement in this AD experimental model. In conclusion, these results could be the therapeutic basis targeting JNK and a possible new diagnostic approach for AD.