JNK mediates synaptic dysfunction caused by A-beta oligomers in Alzheimer disease.

Tiziana Borsello, Universite des Sciences et Technologies de Lille, University Mario Negri, Milan, Italy

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that begins with synaptic dysfunction, which is triggered by soluble toxic oligomeric assemblies of beta-amyloid peptides (A-beta). The molecular mechanisms underlying the synaptic injury remain unclear, but there are increasing evidences of the involvement of mitogen-activated protein kinases (MAPKs). Among these, c-jun N-terminal kinase (JNK) has been extensively studied for its role in AD pathology. To have a deeper insight of the role played by this kinase we set up a new in vitro model of synaptic degeneration following exposure of hippocampal neurons from Brainbow mice with sub-toxic concentrations of synthetic A-beta oligomers. A-beta oligomers caused a strong activation of the JNK pathway the decrease of postsynaptic markers (AMPAR and NMDAR subunits, PSD95 and drebrin). To confirm the key role of JNK in synaptic degeneration induced by A-beta oligomers, we used the specific cell permeable JNK inhibitor peptide, D-JNKI1 to inhibit specifically JNK. Treatment with D-JNKI1 reverted the synaptic degeneration by preventing the loss of dendritic spines in vitro. These in vitro results were confirmed in vivo studies with an AD mouse model (TgCRND8 mice). In the hippocampus of TgCRND8 mice, JNK is activated in the postsynaptic compartment before the onset of the cognitive impairment. D-JNKI1 treatment prevented the loss of postsynaptic proteins and glutamate receptors from the postsynaptic density and the reduction in the size of excitatory synapses as revealed by quantitative electron-microscopy analysis. Noteworthy, the efficacy of the inhibitor D-JNKI1 shows the existence of new therapeutic targets and opens opportunities for the development of innovative approaches to prevent synaptopathy.