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 stress
stimuli, can alter neuronal functions and survival. The JNK cascade plays a crucial role in the
post-synaptic neuronal compartment by altering its structural organization and leading, at worst,
to an overall impairment of neuronal communication. Increasing evidence suggests that synaptic
impairment is the first neurodegenerative event in Alzheimer’s disease (AD). To better elucidate this
mechanism, we longitudinally studied 5xFAD mice at three selected time points representative of
human AD symptom progression. We tested the mice cognitive performance by using the radial
arm water maze (RAWM) in parallel with biochemical evaluations of post-synaptic enriched protein
fraction and total cortical parenchyma. We found that 5xFAD mice presented a strong JNK activation
at 3.5 months of age in the post-synaptic enriched protein fraction. This JNK activation correlates
with a structural alteration of the post-synaptic density area and with memory impairment at this
early stage of the disease that progressively declines to cause cell death. These findings pave the way
for future studies on JNK as a key player in early neurodegeneration and as an important therapeutic
target for the development of new compounds able to tackle synaptic impairment in the early phase
of AD pathology