In the long search for effective therapies against Alzheimer’s disease (AD), most strategies have converged on a single pathological hallmark: amyloid-β (Aβ) plaques. These approaches have delivered only modest clinical benefits, often accompanied by safety concerns. A new study from Monika Chauhan and Komal Singh, working with Dr Pushkar Sharma at the BRIC–National Institute of Immunology, shifts the focus away from plaques and toward the neuronal survival pathways regulated by the E3 ubiquitin ligase AIP4 or Itch. Their work, recently published in iScience, builds on earlier findings that Itch becomes aberrantly activated in response to Aβ, triggering neuronal death through dysregulated cell cycle re-entry. The new study takes a step forward by demonstrating that inhibiting Itch, either genetically or pharmacologically, can reverse cognitive decline in a mouse model of Alzheimer’s disease.
A Molecular Switch Gone Wrong
A key mechanistic insight underpins this study. In AD models, Aβ42 activates the JNK signaling pathway, leading to phosphorylation and autoubiquitination of Itch at specific residues. These modifications hyperactivate the enzyme, promoting degradation of key neuronal survival proteins such as TAp73 and triggering apoptosis. This suggests that Itch plays a central role in Aβ-driven neuronal loss, rather than being a passive bystander.
Two Paths to the Same Target
To test whether Itch could be therapeutically targeted, the researchers adopted a two-pronged strategy.
1. Gene therapy approach
Using adeno-associated virus (AAV) vectors, they delivered loss-of-function mutants of Itch into the brains of transgenic AD mice. These mutants, which were designed to block key phosphorylation and ubiquitination sites, effectively neutralized Itch activity. The result was striking: mice showed significant improvements in spatial learning and working memory, alongside a marked reduction in neuronal apoptosis.
2. Drug repurposing approach
In parallel, the team explored a pharmacological route using clomipramine, a tricyclic antidepressant already approved for psychiatric disorders. Identified in earlier screens as an inhibitor of Itch, clomipramine suppressed Itch activity in neurons, prevented degradation of TAp73, and reduced markers of apoptosis. When administered to AD model mice over 45 days, clomipramine produced robust improvements across multiple behavioral assays indicating recovery of spatial, working, and reference memory.
Neuroprotection Without Touching Plaques
One of the most notable findings is what the intervention does ‘not’ do. Clomipramine does not alter amyloid plaque burden. Instead, it acts downstream of Aβ generation, directly protecting neurons from apoptosis in both the cortex and hippocampus—the regions critical for learning and memory. This indicates neuronal survival can be maintained despite ongoing amyloid pathology.
From Bench to Bedside
Clomipramine has been in clinical use for decades, with a well-characterized safety profile. Its repurposing for Alzheimer’s disease could therefore bypass many early-stage hurdles in drug development. The research team has already secured a U.S. patent for its use in AD. If successful in further validation and clinical studies, this approach could offer a cost-effective alternative to current therapies, which are often expensive and associated with adverse effects.
Basic biology is the foundation of therapeutic innovation
Perhaps the most powerful message of this work lies beyond the specific target or drug. It shows how fundamental insights into molecular mechanisms can open entirely new therapeutic avenues. By identifying Itch as a critical node linking amyloid toxicity to neuronal death, the team has reframed the problem of Alzheimer’s disease. Their study not only proposes a novel target but also demonstrates that intervening at this node can meaningfully alter disease outcomes in vivo.
References:
- Chauhan M, Singh K, Sharma P. Targeting of Itch by clomipramine or gene therapy improves cognitive defects related to Alzheimer’s disease. iScience. 2026;29:115181. doi:10.1016/j.isci.2026.115181
- Chauhan M, Modi PK, Sharma P. Aberrant activation of neuronal cell cycle caused by dysregulation of ubiquitin ligase Itch results in neurodegeneration. Cell Death Dis. 2020;11(6):441. Published 2020 Jun 8. doi:10.1038/s41419-020-2647-1
- Sharma Pushkar and Chauhan Monika (2024) Clomipramine for the treatment of Alzheimer’s disease (US Patent Number. 11,957,692; Granted on 16/04/2024)
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