Distinct disruptions in Land's cycle remodeling of glycerophosphocholines in murine cortex mark symptomatic onset and progression in two Alzheimer's Disease mouse models.

Changes in glycerophosphocholine metabolism are observed in Alzheimer's Disease (AD); however, it is not known whether these metabolic disruptions are linked to cognitive decline. Here, using unbiased lipidomic approaches and direct biochemical assessments, we profiled Land's cycle lipid remodelling in the hippocampus, frontal cortex, and temporal-parietal-entorhinal cortices of human amyloid beta precursor protein (ΑβPP) overexpressing mice. We identified a cortex-specific hypo-metabolic signature at symptomatic onset and a cortex-specific hyper-metabolic signature of Land's cycle glycerophosphocholine remodeling over the course of progressive behavioural decline. When N5 TgCRND8 and ΑβPPS we /PSIdE9 mice first exhibited deficits in the Morris Water Maze, levels of lyso-phosphatidylcholines, LPC(18:0/0:0), LPC(16:0/0:0), LPC(24:6/0:0), LPC(25:6/0:0), the lyso-platelet activating factor (PAF), LPC(O-18:0/0:0), and the PAF, PC(O-22:6/2:0), declined as a result of reduced calcium-sensitive cytosolic phospholipase A2 α (cPLA2 α) activity in all cortices but not hippocampus. Chronic intermittent hypoxia, an environmental risk factor that triggers earlier learning memory impairment in ΑβPPS we /PSIdE9 mice, elicited these same metabolic changes in younger animals. Thus, this lipidomic signature of phenoconversion appears age-independent. By contrast, in symptomatic N5 TgCRND8 mice, cPLA2 α activity progressively increased; overall LPC and LPC(O) and PC(O-18:1/2:0) levels progressively rose. Enhanced cPLA2 α activity was only detected in transgenic mice; however, age-dependent increases in the PAFAH1b α1 to α2 expression ratio, evident in both transgenic and non-transgenic mice, reduced PAF hydrolysis thereby contributing to PAF accumulation. Taken together, these data identify distinct age-independent and age-dependent disruptions in Land's cycle metabolism linked to symptomatic onset and progressive behavioural decline in animals with pre-existing Αβ pathology. This article is protected by copyright. All rights reserved.