An Anti‐Amyloidogenic Approach to Specifically Block Memory Consolidation in Mice for Therapeutic Intervention

Abstract

Post-traumatic stress disorder (PTSD) is a mental health disorder triggered by exposure to a traumatic event, which manifests with anguish, intrusive memories, and negative mood changes. So far, there is no efficient treatment for PTSD other than symptomatic palliative care. However, the cytoplasmic polyadenylation element binding protein-3 (CPEB3) has been recently associated with a potential risk gene for PTSD. Considering that the CPEB3 protein is a functional amyloid whose importance for long-term memory consolidation in mammals is well established, we propose the active (amyloid) state of CPEB3 as a promising potential therapeutic target to investigate the blockade of the consolidation of traumatic memories using the anti-amyloidogenic polyglutamine binding peptide 1 (QBP1). Here we report a genetic preclinical development evaluation in mice of this concept, providing a framework for future pharmacological treatment for PTSD based on the action of the QBP1 peptide. We first characterized the human CPEB3 (hCPEB3) protein in vitro, showing how its amyloid aggregation is inhibited by the active core of QBP1 (QBP1-M8) without affecting other self-assembly processes such as phase separation. Then, we generated and characterized a novel transgenic mouse that constitutively expresses QBP1 in tandem (TgQBP1). TgQBP1 mice exhibit impaired consolidation of simple learning after 24 h, affecting both hippocampus-dependent and aversive memories. While recall of the fear context is reduced-resulting in a lack of extinction-QBP1 does not affect short-term memory. Moreover, under a PTSD-like protocol, TgQBP1 mice showed significant extinction of the traumatic memory and reduced anhedonia compared to WT mice, which showed the expected PTSD-like symptoms of persistent aversive memory and anhedonia. Finally, the analysis of CPEB3 amyloid presence in extracted hippocampal samples showed a correlative decrease in murine CPEB3 oligomerization in the TgQBP1 mice. Taken together, these results strongly suggest that the amyloidogenic blockade of CPEB3 by the QBP1 peptide is a potential avenue for exploring future therapeutic approaches for the prevention and treatment of PTSD, pending validation through post-developmental or pharmacological approaches.