JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model

The c-Jun N-terminal kinases (JNKs) are a family of proteins that, once activated by stressstimuli, can alter neuronal functions and survival. The JNK cascade plays a crucial role in thepost-synaptic neuronal compartment by altering its structural organization and leading, at worst,to an overall impairment of neuronal communication. Increasing evidence suggests that synapticimpairment is the first neurodegenerative event in Alzheimer’s disease (AD). To better elucidate thismechanism, we longitudinally studied 5xFAD mice at three selected time points representative ofhuman AD symptom progression. We tested the mice cognitive performance by using the radialarm water maze (RAWM) in parallel with biochemical evaluations of post-synaptic enriched proteinfraction and total cortical parenchyma. We found that 5xFAD mice presented a strong JNK activationat 3.5 months of age in the post-synaptic enriched protein fraction. This JNK activation correlateswith a structural alteration of the post-synaptic density area and with memory impairment at thisearly stage of the disease that progressively declines to cause cell death. These findings pave the wayfor future studies on JNK as a key player in early neurodegeneration and as an important therapeutictarget for the development of new compounds able to tackle synaptic impairment in the early phaseof AD pathology