Stabilization of the retromer with tool compounds ameliorates synaptic dysfunction in the Alzheimer's disease model 5xFAD

Synaptic dysfunction is an early hallmark of AD pathology. It is characterized by the disruption of synaptic transmission and plasticity. Endosomal trafficking is central to this process. The retromer complex orchestrates the movement of vesicle contents, either pushing them back to the Golgi, degrading them, or recycling them to the plasma membrane. Variations in the cargo recognition component of the retromer, VPS35, have been associated with both Parkinson's (D620N mutation, PARK17) and Alzheimer's (L625P mutation). Extensive pathophysiological studies have been conducted on Parkinson's disease, but not on Alzheimer's. In the latter, retromer in microglia has been identified as critical for their proper activation. Abnormal levels of retromer proteins have been detected in early AD patients. Tool compounds can stabilize the retromer which reduce pathogenic Abeta production in vitro. To study the potential involvement of VPS35 in Alzheimer's and shed light on any neuroprotective role, we investigated the acute effects of these tool compounds in 5xFAD. Our findings suggest microglial activation, as previously described, and a compensatory effect on early synaptic dysfunction, particularly around genes involved in long-term potentiation.