Polyunsaturated fatty acids in lipid membranes regulate human neuronal function and amyloid-β production.

The effects and mechanisms of polyunsaturated fatty acids (PUFAs) including docosahexaenoic acid (DHA) and arachidonic acid (ARA) contained in the lipid membrane of neurons in the production of amyloid β (Aβ), a pathogenic molecule in Alzheimer's disease (AD), remain unclear. In this study, we cultured human cortical neurons differentiated from induced pluripotent stem cells (iPSCs) under conditions of PUFA deficiency being progressively alleviated. Under PUFA-deficient conditions, increasing the total PUFA composition ratio in the lipid membrane enhanced membrane fluidity and reduced Aβ production. Furthermore, in conditions where the overall PUFA deficiency was resolved, altering the specific ratios of DHA and ARA promoted the synchronous activity and morphological complexity of neuronal cells while maintaining consistent membrane fluidity. These findings demonstrate that the overall PUFA composition in the lipid membrane as well as the specific ratios of DHA and ARA within the total PUFAs regulate neuronal function and pathophysiology.