Targeting of Itch by clomipramine or gene therapy improves cognitive defects related to Alzheimer's disease.

We propose a therapeutic strategy against Alzheimer's disease (AD), which involves targeting E3 ubiquitin ligase AIP4 or Itch. Previous studies have shown that Itch is aberrantly activated in cortical neurons of a mouse model of AD and contributes to neuronal death. We used a two-pronged approach to target Itch in a mouse model for AD: (1) adeno-associated virus (AAV) expressing loss-of-function mutants of Itch and (2) clomipramine, a tricyclic antidepressant, which is an Itch inhibitor. Both treatments significantly improved learning and memory associated with AD mice. A reversal in neuronal apoptosis was observed in AD mouse brain, which explained the improvement in cognition. Clomipramine was able to inhibit Itch in neurons and prevent their apoptosis in response to Aβ42. Given that clomipramine is being used against psychiatric disorders, this drug may be repurposed for use against AD.