NRF2 deficiency is associated with synaptic alterations and ether-linked phospholipid imbalance in the hippocampus

Synaptic loss is a key factor in the cognitive decline observed during aging and in neurodegenerative diseases such as dementia, where synaptopathy plays a central role in hippocampal dysfunction. In this study, we investigated the role of NRF2, a master regulator of cellular homeostasis, in maintaining synaptic integrity. We assessed synaptic contacts both in vitro and in vivo and found that NRF2 deficiency leads to a significant reduction in vGLUT1 levels, accompanied by a decrease in the number of synaptic contacts. Because synapses are subject to highly dynamic membrane remodeling processes, we analyzed the lipid composition of hippocampi and synaptosomes from NRF2-deficient and wild-type mouse littermates. Our results revealed an accumulation of ether-linked phospholipids in NRF2-deficient mice. When primary neuronal and organotypic cultures were exposed to an ether-lipid precursor, synaptic density decreased. By contrast, the NRF2 activator 6-(methylsulfinyl)hexyl isothiocyanate (6-MSITC or hexaraphane) prevented synaptic loss. Although ether lipids are abundant components of neuronal membranes, their specific role in synaptic function and in age-related loss of homeostatic balance remains poorly understood. This study is the first to demonstrate that NRF2 plays an essential role in preserving synaptic homeostasis through lipid metabolism, suggesting its relevance in the context of aging and neurodegenerative diseases.