Oxidized phospholipids as novel mediators of neurodegeneration

Neurodegeneration drives the progression of many neurological diseases. Inflammation and oxidative stress occurring in the CNS promote lipid peroxidation, leading to the generation of oxidized phospholipids such as oxidized phosphatidylcholines (OxPCs). OxPCs have been proposed as biomarkers of oxidative stress, where their detection in lesions in multiple sclerosis (MS), frontotemporal lobe dementia, spinal cord injury, and amyotrophic lateral sclerosis (ALS) implies that oxidative insult had occurred. However, recent findings highlight OxPCs as potent neurotoxic species requiring neutralization by microglia. Here, we summarize the science of OxPCs, including lessons from non-CNS diseases. We discuss the potential of OxPCs as common drivers of injury across neurological conditions and encourage investigations of OxPCs as novel neurotoxins. Lipid peroxidation products such as oxidized phospholipids are associated with inflammation and neurodegeneration in diseases of the CNS.Oxidized phosphatidylcholines (OxPCs) are among the best-understood class of oxidized phospholipids. They are found in lesions of multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal lobe dementia, and spinal cord injury.In the mouse spinal cord, OxPC deposition causes demyelination and neurodegeneration, and requires triggering receptor expressed on myeloid cells 2 (TREM2)-expressing microglia for clearance.OxPCs are cytotoxic and promote inflammation and pathology in multiple non-CNS diseases. Additional investigations to understand OxPC heterogeneity, functions, and mechanisms in the CNS may uncover new therapeutics for neurodegenerative diseases.