Background: RNA editing at the Q/R site of GluA2 occurs with ~99% efficiency in the healthy brain, so that the majority of AMPARs contain GluA2(R) instead of the exonically encoded GluA2(Q). Reduced Q/R site editing increases AMPA receptor calcium permeability and leads to dendritic spine loss, neurodegeneration, seizures and learning impairments. Furthermore, GluA2 Q/R site editing is impaired in Alzheimer’s disease (AD), raising the possibility that unedited GluA2(Q)-containing AMPARs contribute to synapse loss and neurodegeneration in AD. If true, then inhibiting expression of unedited GluA2(Q), while maintaining expression of GluA2(R), may be a novel strategy of preventing synapse loss and neurodegeneration in AD. Methods: We engineered mice with the ‘edited’ arginine codon (CGG) in place of the unedited glutamine codon (CAG) at position 607 of the Gria2 gene. We crossbred this line with the J20 mouse model of AD and conducted anatomical, electrophysiological and behavioural assays to determine the impact of eliminating unedited GluA2(Q) expression on AD-related phenotypes. Results: Eliminating unedited GluA2(Q) expression in AD mice prevented dendritic spine loss and hippocampal CA1 neurodegeneration as well as improved working and reference memory in the radial arm maze. These phenotypes were improved independently of Aβ pathology and ongoing seizure susceptibility. Surprisingly, our data also revealed increased spine density in non-AD mice with exonically encoded GluA2(R) as compared to their wild-type littermates, suggesting an unexpected and previously unknown role for unedited GluA2(Q) in regulating dendritic spines. Conclusion: The Q/R editing site of the AMPA receptor subunit GluA2 may act as an epigenetic switch that regulates dendritic spines, neurodegeneration and memory deficits in AD.

Minimally invasive interventions using drug‐eluting stents or balloons are a first‐line treatment for certain occlusive cardiovascular diseases, but the major long‐term cause of failure is neointimal hyperplasia (NIH). The drugs eluted from these devices are non‐specific anti‐proliferative drugs, such as paclitaxel (PTX) or sirolimus (SMS), which do not address the underlying inflammation. MCC950 is a selective inhibitor of the NLRP3‐inflammasome, which drives sterile inflammation commonly observed in NIH. Additionally, in contrast to broad‐spectrum anti‐inflammatory drugs, MCC950 does not compromise global immune function due this selective activity. In this study, MCC950 is found to not impact the viability, integrity, or function of human coronary endothelial cells, in contrast to the non‐specific anti‐proliferative effects of PTX and SMS. Using an in vitro model of NLRP3‐mediated inflammation in murine macrophages, MCC950 reduced IL‐1β expression, which is a key driver of NIH. In an in vivo mouse model of NIH in vascular grafts, MCC950 significantly enhanced re‐endothelialization and reduced NIH compared to PTX or SMS. These findings show the effectiveness of a targeted anti‐inflammatory drug‐elution strategy with significant implications for cardiovascular device intervention.

• Revascularization for PAD has been characterized by the adaptation of technologies from the treatment of CAD, with few therapies specifically developed for PAD. • In light of recent increases in all-cause mortality driven by endovascular PAD interventions that employ elution of antiproliferative agents, this review highlights the unmet need to address underlying local inflammation and proposes an alternative therapeutic approach. • Development of next-generation PAD-specific endovascular interventions will benefit from integration of specialized immunotherapies that target macrophage polarization and focus on vessel healing.