Aberrant glycerophosphocholine metabolism is a primary and targetable pathology in Alzheimer Disease

Glycerophospholipids are often overlooked as immediate response elements yet they exert fundamental control over cell viability. They represent the major building blocks of biological membranes and modulate membrane trafficking. Enzymatic processing of choline‐containing membrane phospholipids by cytosolic phospholipase A2 (cPLA2) generates powerful smaller intracellular second messengers (~450–600 Da) as well as arachidonic acid and its metabolites. Individual isoforms control distinct cellular processes, but little is known about how they respond to normal brain functions and neurodegenerative disease state. Recent advances in mass spectrometry are enabling large‐scale profiling of individual lipid isoforms in brain tissue and cells. We capitalize on these advances to address the question whether aberrant membrane lipid metabolism is a risk factor for neurodegenerative disease. Here, we employed high performance liquid chromatography combined with electrospray ionization mass spectrometry (LC‐ESI‐MS) to profile glycerophosphocholine second messenger metabolism in the post‐mortem human entorhinal cortex and hippocampus, as well as in the temporal cortex and hippocampus of C57BL/6 × 129SV/J hybrid mice over the course of a 24 h period.