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

## TL;DR

This study shows that targeting the Itch protein with gene therapy or the drug clomipramine can improve cognitive issues in a mouse model of Alzheimer’s disease.

## Contribution

The study introduces Itch as a novel therapeutic target for Alzheimer’s disease using gene therapy and drug repurposing.

## Key findings

- Loss-of-function Itch mutants reversed cognitive defects in AD mice.
- Clomipramine inhibited Itch and prevented neuronal apoptosis in AD mouse brains.
- Itch inhibition improved learning and memory in AD models.

## Abstract

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.

•Ubiquitin ligase Itch is aberrantly activated in response to Aβ42 in the AD mouse model•Loss-of-function mutants of Itch reversed cognitive defects in the AD mouse model•Clomipramine improved cognition and prevented apoptosis in AD mouse brain•Targeting Itch is a promising therapeutic pathway for Alzheimer’s disease

Ubiquitin ligase Itch is aberrantly activated in response to Aβ42 in the AD mouse model

Loss-of-function mutants of Itch reversed cognitive defects in the AD mouse model

Clomipramine improved cognition and prevented apoptosis in AD mouse brain

Targeting Itch is a promising therapeutic pathway for Alzheimer’s disease

Neuroscience; Molecular neuroscience