Enhancing Retromer Complex Stability Ameliorates Synaptic Dysfunction in a Mouse Model of Alzheimer's Disease

Synaptic dysfunction is an early hallmark of Alzheimer's disease, characterized by the disruption of synaptic transmission and plasticity. Central to these processes is endosomal trafficking, mediated by the retromer complex, which orchestrates the movement of vesicle contents for recycling to the plasma membrane, return to the Golgi, or degradation. Variants of VPS35, the cargo recognition component of the retromer complex, have been linked to neurodegenerative diseases, including Parkinson's disease (PARK17, D620N mutation) and Alzheimer's disease (L625P mutation). While substantial research has focused on Parkinson's, the role of VPS35 in Alzheimer's has been less explored. This study investigates the acute neuroprotective effects of retromer-stabilizing compounds in the 5xFAD mouse model of Alzheimer's. Our results reveal that stabilization of the retromer complex not only mitigates pathogenic Aß production mechanisms but also compensates for early synaptic dysfunction and microglial activation. Specifically, we observed significant modulation of genes involved in long-term potentiation and a reduction in abnormal retromer-associated cargos. These findings highlight the potential of retromer stabilisation as atherapeutic strategy to address fundamental pathological pathological processes in Alzheimer's disease. Overall design: To investigate the pathophysiological changes in AD that can be targeted by retromer stabilization, we delivered two tool compounds (R55 and R33) and vehicle intracranially by sterotaxic microinjection to one hemisphere of 5xFAD transgenic mice. To verify the effects of the surgery, the other hemisphere was used. We collected RNA from the cortex of both hemispheres, built a library and performed RNAseq.