Deficiency of Lipoprotein Lipase in Neurons Decreases AMPA Receptor Phosphorylation and Leads to Neurobehavioral Abnormalities in Mice.
Alterations in lipid metabolism have been found in several neurodegenerative disorders, including Alzheimer's disease. Lipoprotein lipase (LPL) hydrolyzes triacylglycerides in lipoproteins and regulates lipid metabolism in multiple organs and tissues, including the central nervous system (CNS). Though many brain regions express LPL, the functions of this lipase in the CNS remain largely unknown. We developed mice with neuron-specific LPL deficiency that became obese on chow by 16 wks in homozygous mutant mice (NEXLPL-/-) and 10 mo in heterozygous mice (NEXLPL+/-). In the present study, we show that 21 mo NEXLPL+/- mice display substantial cognitive function decline including poorer learning and memory, and increased anxiety with no difference in general motor activities and exploratory behavior. These neurobehavioral abnormalities are associated with a reduction in the 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor subunit GluA1 and its phosphorylation, without any alterations in amyloid β accumulation. Importantly, a marked deficit in omega-3 and omega-6 polyunsaturated fatty acids (PUFA) in the hippocampus precedes the development of the neurobehavioral phenotype of NEXLPL+/- mice. And, a diet supplemented with n-3 PUFA can improve the learning and memory of NEXLPL+/- mice at both 10 mo and 21 mo of age. We interpret these findings to indicate that LPL regulates the availability of PUFA in the CNS and, this in turn, impacts the strength of synaptic plasticity in the brain of aging mice through the modification of AMPA receptor and its phosphorylation.
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, School of Medicine, Aurora, CO 80045, United States of America.
Tian
T
Yu
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, School of Medicine, Aurora, CO 80045, United States of America.
Matthew D
MD
Taussig
Department of Pharmacology, University of California Irvine, CA 92617, United States of America.
Nicholas V
NV
DiPatrizio
Department of Pharmacology, University of California Irvine, CA 92617, United States of America.
Giuseppe
G
Astarita
Department of Pharmacology, University of California Irvine, CA 92617, United States of America.
Daniele
D
Piomelli
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, School of Medicine, Aurora, CO 80045, United States of America.
Bryan C
BC
Bergman
Department of Pharmacology, University of Colorado, School of Medicine, Aurora, CO 80045, United States of America.
Mark L
ML
Dell'Acqua
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, School of Medicine, Aurora, CO 80045, United States of America.
Robert H
RH
Eckel
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, School of Medicine, Aurora, CO 80045, United States of America.
Hong
H
Wang
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000378:metabolism; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D015870:Gene Expression; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism; D007858:Learning; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000172:deficiency* / Q000235:genetics; D008568:Memory; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation; D021122:Protein Subunits / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D021122:Protein Subunits; D018091:Receptors, AMPA; D008071:Lipoprotein Lipase