title: Apolipoprotein CI knock-out mice display impaired memory functions.
abstract: The ε4 allele of apolipoprotein E (APOE4), which is a well established genetic risk factor for development of Alzheimer's disease (AD), is in genetic disequilibrium with the H2 allele of apolipoprotein C1 (APOC1), giving rise to increased expression of apoC-I. This raises the possibility that the H2 allele of APOC1, either alone or in combination with APOE4, provides a major risk factor for AD. In line herewith, we previously showed that mice overexpressing human APOC1 display impaired learning and memory functions. Here, we tested the hypothesis that the absence of Apoc1 expression in mice may improve memory functions. In contrast with our expectations, Apoc1(-/-) mice showed impaired hippocampal-dependent memory functions, as judged from their performance in the object recognition task (p < 0.001) as compared to their wild-type littermates. No gross changes in brain morphology or in brain sterol concentrations were detected in knockout mice compared to wild-type littermates. Apoc1 deficiency reduced the expression of ApoE mRNA (-25%, p < 0.05), but not ApoE protein levels. In line with a role for apoC-I in inflammatory processes, we observed significantly increased mRNA concentrations of the proinflammatory marker tumor necrosis factor α and oxidative stress related heme oxygenase 1 (Hmox1) in the absence of glial activation. In conclusion, the absence of ApoC-I results in impaired memory functions, which is, together with previous data, suggestive of an important, bell-shaped gene-dose dependent role for ApoC-I in appropriate brain functioning. The relative contributions of the H2 allele of APOC1 and/or APOE4 in the risk assessment in AD remain to be determined.
authors.affiliation: Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, TNO-Quality of Life, Gaubius Laboratory, The Netherlands.
authors.forename: Jimmy F P
authors.initials: JF
authors.lastname: Berbée
authors.forename: Tim
authors.initials: T
authors.lastname: Vanmierlo
authors.forename: Karlygash
authors.initials: K
authors.lastname: Abildayeva
authors.forename: Arjan
authors.initials: A
authors.lastname: Blokland
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Jansen
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Thomas
authors.initials: T
authors.lastname: Gautier
authors.forename: Eric
authors.initials: E
authors.lastname: Sijbrands
authors.forename: Jos
authors.initials: J
authors.lastname: Prickaerts
authors.forename: M'hamed
authors.initials: M
authors.lastname: Hadfoune
authors.forename: Frans C S
authors.initials: FC
authors.lastname: Ramaekers
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.forename: Monique
authors.initials: M
authors.lastname: Mulder
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D053302:Apolipoprotein C-I / Q000172:deficiency*; D053327:Apolipoprotein E4 / Q000378:metabolism; D001921:Brain; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D008297:Male; D008569:Memory Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D013239:Stereotyped Behavior / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053302:Apolipoprotein C-I; D053327:Apolipoprotein E4; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha