Apolipoprotein CI Knock-Out Mice Display Impaired Memory Functions

Article type: Research Article

Authors: Berbée, Jimmy F.P.^{a; 1} | Vanmierlo, Tim^{b; c; 1} | Abildayeva, Karlygash^d | Blokland, Arjan^e | Jansen, Paula J.^d | Lütjohann, Dieter^b | Gautier, Thomas^f | Sijbrands, Eric^g | Prickaerts, Jos^c | Hadfoune, M'hamed^h | Ramaekers, Frans C.S.^d | Kuipers, Folkert^f | Rensen, Patrick C.N.^a | Mulder, Monique^{d; g; *}

Affiliations: [a] Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, and Department of Biomedical Research, TNO-Quality of Life, Gaubius Laboratory, Leiden, The Netherlands | [b] Department of Clinical Chemistry and Pharmacology, University of Bonn, Germany | [c] Department of Neuroscience, Maastricht University, The Netherlands | [d] Department of Molecular Cell Biology, Maastricht University, The Netherlands | [e] Department of Neuropsychology and Psychopharmacology, Maastricht University, The Netherlands | [f] Department of Pediatrics, University Medical Center Groningen, The Netherlands | [g] Department of Internal Medicine, Division of Pharmacology, Vascular and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The Netherlands | [h] Department of General Surgery, Maastricht University, The Netherlands

Correspondence: [*] Correspondence to: Dr. Monique Mulder, Erasmus Medical Center, Department of Internal Medicine, Division of Pharmacology, Vascular and Metabolic Diseases, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. Tel.: +31(0)107032707; Fax: +31(0)107033964; E-mail: [email protected].

Note: [1] Authors contributed equally.

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.

Keywords: APOC1, apolipoprotein C-I, cholesterol, cognition and brain, memory

DOI: 10.3233/JAD-2010-100576

Journal: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 737-747, 2011