title: LDL receptor deficiency results in decreased cell proliferation and presynaptic bouton density in the murine hippocampus.
abstract: An aberrant cholesterol metabolism in the brain may contribute to the pathogenesis of Alzheimer's disease (AD). The LDL receptor (LDLR) regulates plasma cholesterol levels and recently we and others obtained evidence that it is also involved in regulating brain cholesterol homeostasis. Moreover, we found that LDLR-deficient mice display impaired spatial memory. Because cholesterol, in part derived from cellular uptake via LDLR, is required for peripheral cell proliferation and growth, we examined the effect of absence of the LDLR on hippocampal proliferation and the density of synaptic connections. Mice deficient for the LDLR displayed a reduced number of proliferating (BrdU-labeled) cells in the hippocampus as compared to wild type control mice. In addition, the number of synaptophysin-immunoreactive presynaptic boutons in the hippocampal CA1 and the dentate gyrus (DG) areas, but not in cortical areas, was lower in the LDLR-knockout mice than in the control mice. In vitro experiments showed that LDLR activity is increased when cell growth is enhanced by the addition of N2 supplement. This further supports a role for the LDLR in the outgrowth of neurites. These findings support the notion that, similar to its role in the periphery, the LDLR is important for the cellular uptake of cholesterol in the brain and that disturbance of this process affects neuronal plasticity.
authors.affiliation: Department of Molecular Cell Biology, University of Maastricht, Maastricht, The Netherlands. M.Mulder@NP.unimaas.nl
authors.forename: Monique
authors.initials: M
authors.lastname: Mulder
authors.forename: Guido
authors.initials: G
authors.lastname: Koopmans
authors.forename: Guido
authors.initials: G
authors.lastname: Wassink
authors.forename: Ghais
authors.initials: G
authors.lastname: Al Mansouri
authors.forename: Marie-Lune
authors.initials: ML
authors.lastname: Simard
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Jos
authors.initials: J
authors.lastname: Prickaerts
authors.forename: Arjan
authors.initials: A
authors.lastname: Blokland
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001973:Bromodeoxyuridine; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism; D018891:Dentate Gyrus / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure; D015536:Down-Regulation / Q000235:genetics; D006624:Hippocampus / Q000254:growth & development* / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009434:Neural Pathways / Q000254:growth & development* / Q000378:metabolism* / Q000648:ultrastructure; D009473:Neuronal Plasticity / Q000235:genetics; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D011973:Receptors, LDL / Q000235:genetics*; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D011973:Receptors, LDL; D016708:Synaptophysin; D002784:Cholesterol; D001973:Bromodeoxyuridine