TY - JOUR
T1 - Distinct disruptions in Land's cycle remodeling of glycerophosphocholines in murine cortex mark symptomatic onset and progression in two Alzheimer's disease mouse models
AU - Granger, Matthew W.
AU - Liu, Hui
AU - Fowler, Caitlin F.
AU - Blanchard, Alexandre P.
AU - Taylor, Matthew W.
AU - Sherman, Samantha P.M.
AU - Xu, Hongbin
AU - Le, Weidong
AU - Bennett, Steffany A.L.
N1 - Funding Information:
MWG and SPMS received Ontario Graduate Scholarships; APB received an Alzheimer Society of Canada studentship; MT received a Natural Science Research Council studentship. This study was funded by a University of Ottawa and Shanghai Jiao Tong University Joint Medical Research Program grant to WL and SALB, Canadian Institute of Health Research (MOP#311838) and Natural Science Research Council operating grant (#5377) to SALB, and Chinese National Sciences Foundation (No. 81370470, No. 81430021), National Basic Research Program (No. 2011CB510003 and No. 81771521), and Collaborative Innovation Center for Brain Science to WL We thank Louis Dacquay for confirmatory data analysis replicating these analyses performed as part of his participation in our graduate class BCH8110 (University of Ottawa). The authors have no conflict of interest to report.
Publisher Copyright:
© 2018 International Society for Neurochemistry
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/5
Y1 - 2019/5
N2 - 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 (ΑβPP) 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 ΑβPPSwe/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-dependent cytosolic phospholipase A2α (cPLA2α) activity in all cortices but not hippocampus. Chronic intermittent hypoxia, an environmental risk factor that triggers earlier learning memory impairment in ΑβPPSwe/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, cPLA2α activity progressively increased; overall Lyso-phosphatidylcholines (LPC) and LPC(O) and PC(O-18:1/2:0) levels progressively rose. Enhanced cPLA2α activity was only detected in transgenic mice; however, age-dependent increases in the PAF acetylhydrolase 1b 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 behavioral decline in animals with pre-existing Αβ pathology. Open science badges: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. (Figure presented.).
AB - 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 (ΑβPP) 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 ΑβPPSwe/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-dependent cytosolic phospholipase A2α (cPLA2α) activity in all cortices but not hippocampus. Chronic intermittent hypoxia, an environmental risk factor that triggers earlier learning memory impairment in ΑβPPSwe/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, cPLA2α activity progressively increased; overall Lyso-phosphatidylcholines (LPC) and LPC(O) and PC(O-18:1/2:0) levels progressively rose. Enhanced cPLA2α activity was only detected in transgenic mice; however, age-dependent increases in the PAF acetylhydrolase 1b 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 behavioral decline in animals with pre-existing Αβ pathology. Open science badges: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. (Figure presented.).
KW - Alzheimer's disease
KW - glycerophosphocholine
KW - hypoxia
KW - lipidomics
KW - phospholipase A
KW - platelet-activating factor
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U2 - 10.1111/jnc.14560
DO - 10.1111/jnc.14560
M3 - Article
C2 - 30040874
AN - SCOPUS:85056162676
VL - 149
SP - 499
EP - 517
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 4
ER -