Decreased DHA-containing phospholipids in the neocortex of dementia with Lewy bodies are associated with soluble A beta(42), phosphorylated alpha-synuclein, and synaptopathology

Docosahexaenoic acid (DHA) is an essential omega-3 polyunsaturated fatty acid implicated in cognitive functions by promoting synaptic protein expression. While alterations of specific DHA-containing phospholipids have been described in the neocortex of patients with Alzheimer's disease (AD), the status of these lipids in dementia with Lewy bodies (DLB), known to manifest aggregated alpha-synuclein-containing Lewy bodies together with variable amyloid pathology, is unclear. In this study, post-mortem samples from the parietal cortex of 25 DLB patients and 17 age-matched controls were processed for phospholipidomics analyses using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform. After controlling for false discovery rate, six out of the 46 identified putative DHA-phospholipid species were significantly decreased in DLB, with only one showing increase. Altered putative DHA-phospholipid species were subsequently validated with further LC-MS/ MS measurements. Of the DHA-containing phospholipid (DCP) species showing decreases, five negatively correlated with soluble beta-amyloid (A beta 42) levels, whilst three also correlated with phosphorylated alpha-synuclein (all p < 0.05). Furthermore, five of these phospholipid species correlated with deficits of presynaptic Rab3A, postsynaptic neurogranin, or both (all p < 0.05). Finally, we found altered immunoreactivities of brain lysolipid DHA transporter, MFSD2A, and the fatty acid binding protein FABP5 in DLB parietal cortex. In summary, we report alterations of specific DCP species in DLB, as well as their associations with markers of neuropathological burden and synaptopathology. These results support the potential role of DHA perturbations in DLB as well as therapeutic targets.

Automated summary

In this study, the authors found altered specific DHA-containing phospholipids in the cortex of patients with dementia with Lewy bodies (DLB) through phospholipidomics analysis. These alterations were associated with markers of neuropathological burden and synaptopathology. Furthermore, changes in the immunoreactivities of brain lysolipid DHA transporter and fatty acid binding protein were also observed in the DLB cortex.