Biology subjects

McGreevy, K. R.

Publications and source records attributed to McGreevy, K. R..

3 recordsLinked to original sources

bioRxiv2025

An anti-amyloidogenic approach to specifically block memory consolidation in mice for therapeutic intervention

Post-traumatic stress disorder (PTSD) is a mental health disorder triggered by the 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 to a potential risk gene for PTSD. Considering that 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 therapeutic target to block the consolidation of traumatic memories through by the anti-amyloidogenic polyglutamine binding peptide 1 (QBP1). Here we report a preclinical development in mice of this 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 have shown that the consolidation of simple learning is impaired after 24 h for both hippocampal-dependent and aversive memories and that it is limited to new learned memories and has no effect on short-term memory. Furthermore, fear induced anxiety was reduced in comparison to WT mice, suggesting that PTSD-like symptoms are also being ameliorated. Intriguingly, we found that aversive memories seem to be more strongly affected in younger mice. Finally, the analysis of CPEB3 amyloid presence in hippocampal extracted samples showed a correlative decrease in murine CPEB3 oligomerization in the TgQBP1 mice. Taking together, these results strongly suggest that the amyloidogenic blockage of CPEB3 by QBP1 peptide is a potential drug for the prevention and treatment of PTSD.

neuroscience↗

bioRxiv2023

Transgenerational effects of exercise on mouse brain and cognition

Lifestyle induces long lasting effects on brain and cognition, with some interventions like stress including transgenerational inheritance mediated by epigenetic mechanisms. Physical exercise is one lifestyle intervention driving robust improvements of cognition, including intergenerational transmission to the litter. However, little is known about whether exercise effects are transgenerationally transmitted. Here we analyzed adult hippocampal neurogenesis (AHN) and behavioral phenotype of sedentary adult male mice of F2 generation of exercised grandfathers (F0). Both F1 and F2 were sedentary, while F0 performed moderate exercise. We found F2 mice from exercised F0 acquired and recalled both spatial and non-spatial information better than F2 from sedentary F0. Contextual fear conditioning was not affected, together with no differences in AHN markers. Hippocampal smallRNAseq analysis revealed 35 significant differentially expressed (sDE) microRNAs (miRNAs) associated to relevant brain function families. Moreover, 11 of the 35 miRNAs target gene sets were found also enriched in F0 and F1, as well as target genes of 6 of them were differentially expressed also in F0 or F1. One of these 6 is miRNA-144, that together with miRNA-298 were found inversely correlated to cognitive index in F2. These results demonstrate that transgenerational transmission of the effects of exercise on specific cognitive tasks persists after two generations, even though some cellular changes induced in F1 vanish in F2. Thus, they suggest moderate exercise training has longer-lasting effects than previously thought, probably mediated by a small group of miRNAs acting across generations, and this is worth taking into account in public health programs.

neuroscience↗

bioRxiv2020

An Anti-amyloidogenic treatment to specifically block the consolidation of traumatic events in mouse

Post-traumatic stress disorder (PTSD) is a mental health disorder triggered by the exposure to a traumatic event that manifests with anguish, intrusive memories and negative mood changes. So far, there is no efficient treatment for PTSD other than symptomatic palliative care. Based on the implication of the functional amyloid cytoplasmic polyadenylation element binding protein-3 (CPEB3) in the consolidation of memory, we propose its active amyloid state as a possible therapeutic target by blocking the consolidation of traumatic memories through polyglutamine binding peptide 1 (QBP1), an inhibitor of the amyloid oligomerization previously investigated in Drosophila. To test this idea in mammals, here we have developed a transgenic mouse that constitutively expresses QBP1 peptide. We first assessed the innocuousness of this peptide for the normal development of the animal, which also showed normal locomotor activity and anxiety. By performing a battery of standard memory paradigms, we then showed that hippocampal-dependent and aversive memories were impaired in the QBP1 mice. Furthermore, protein expression in the hippocampi of experienced mice showed that QBP1 mice do not increase their levels of amyloid oligomerization, evincing the blockade of the CPEB3 protein in its inactive state. The ability of QBP1 to block aversive memories in mice represents the proof of concept of a novel pharmacological approach for prophylaxis and therapy of acute stress and post-traumatic stress disorders.

animal behavior and cognition↗