| First Author | Granger MW | Year | 2018 |
| Journal | J Neurochem | PubMed ID | 30040874 |
| Mgi Jnum | J:272683 | Mgi Id | MGI:6284972 |
| Doi | 10.1111/jnc.14560 | Citation | Granger MW, et al. (2018) Distinct disruptions in Land's cycle remodeling of glycerophosphocholines in murine cortex mark symptomatic onset and progression in two Alzheimer's disease mouse models. J Neurochem |
| abstractText | Changes in glycerophosphocholine metabolism are observed in Alzheimer's disease; 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 remodeling in the hippocampus, frontal cortex, and temporal-parietal-entorhinal cortices of human amyloid beta precursor protein (AlphabetaPP) over-expressing 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 behavioral decline. When N5 TgCRND8 and AlphabetaPP(S) (we) /PSI(dE9) 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-dependent cytosolic phospholipase A2 alpha (cPLA2 alpha) activity in all cortices but not hippocampus. Chronic intermittent hypoxia, an environmental risk factor that triggers earlier learning memory impairment in AlphabetaPP(S) (we) /PSI(dE9) 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 alpha activity progressively increased; overall Lyso-phosphatidylcholines (LPC) and LPC(O) and PC(O-18:1/2:0) levels progressively rose. Enhanced cPLA2 alpha activity was only detected in transgenic mice; however, age-dependent increases in the PAF acetylhydrolase 1b alpha1 to alpha2 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 behavioral decline in animals with pre-existing Alphabeta pathology. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/. |
