It is critical for the neuronal cell cycle to remain suppressed in terminally differentiated neurons as its activation results in aberrant cell cycle re-entry that causes neuronal apoptosis (CRNA), which has been observed in several neurodegenerative disorders like Alzheimer's disease (AD). In the present study, we report that E3 ubiquitin ligase Itch is a major regulator of CRNA and elucidated the mechanism via which it is regulated in this process. Neurotoxic amyloid peptide Aβ42-treated neurons or neurons from an AD transgenic mouse model (TgAD) exhibited aberrant activation of the JNK pathway which resulted in the hyperphosphorylation of Itch. The phosphorylation of Itch primes it for autoubiquitination, which is necessary for its activation. These post-translational modifications of Itch facilitate its interaction with TAp73 resulting in its degradation. These series of events are critical for Itch-mediated CRNA and its phosphorylation and autoubiquitination site mutants reversed this process and were neuroprotective. These studies unravel a novel pathway via which neurodegeneration in AD and possibly other related disorders may be regulated by aberrant regulation of the neuronal cell cycle.