Alterations in Brain Cholesterol Metabolism in the APPSLxPS1mut mouse, a Model for Alzheimer's Disease

Issue title: Similarities and Differences Between Mild Cognitive Impairment and Alzheimer's Disease

Guest editors: Mark A. Lovell

Article type: Research Article

Authors: Vanmierlo, Tim^{a; b} | Bloks, Vincent W.^c | van Vark-van der Zee, Leonie C.^d | Rutten, Kris^a | Kerksiek, Anja^b | Friedrichs, Silvia^b | Sijbrands, Eric^d | Steinbusch, Harry W.^a | Kuipers, Folkert^c | Lütjohann, Dieter^b | Mulder, Monique^{a; d; *}

Affiliations: [a] Department of Neuroscience, Maastricht University, Maastricht, The Netherlands | [b] Institute of Clinical Chemistry and Pharmacology, University of Bonn, Bonn, Germany | [c] Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands | [d] Department of Internal Medicine, Division of Pharmacology, Vascular and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The Netherlands | Sanders-Brown Center on Aging and Alzheimer's Disease Center, Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA

Correspondence: [*] Corresponding author: Dr. M. 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 107032707; Fax: +31 107033964; E-mail: m.t.mulder@erasmusmc.nl.

Note: [] Communicated by Robert Friedland

Abstract: Disturbances in cerebral cholesterol metabolism have been implicated in the pathogenesis of Alzheimer's disease (AD). Here, we provide evidence that alterations in brain cholesterol homeostasis also can be a consequence of disease progression. We found that APPSLxPS1mut mice, at the age of 9 months when AD-like pathology starts to develop, display increased levels of the cholesterol precursor desmosterol and of the cholesterol metabolite 27-hydroxy(OH)cholesterol in their cerebellum in comparison with wild-type controls. At the age of 21 months, when APPSLxPS1mut brain contains abundant amyloid deposits, desmosterol levels had further increased (> 200% in comparison with wild-type mice) in all brain regions examined. 24(S)-OHcholesterol levels were increased in hippocampus and cerebellum of the APPSLxPS1mut mice, while 27-OHcholesterol levels were increased in cerebellum exclusively. Brain cholesterol levels remained unaffected. In line with the fact that desmosterol and 24(S)-OHcholesterol are Liver X Receptor (LXR) activators, the LXR-target genes Abca1 and Apoc1 were upregulated predominantly in hippocampus of APPSLxPS1mut mice at both ages evaluated. The reduced expression of the enzyme that converts desmosterol into cholesterol, the Selective AD indicator 1 gene (Seladin-1/Dhcr24), in both cortex and cerebellum may underlie the increased desmosterol levels in 21 month-old APPSLxPS1mut mice.

Keywords: APPSLxPS1mut, Alzheimer's disease, brain cholesterol metabolism, LXR, oxysterols, seladin

DOI: 10.3233/JAD-2010-1209

Journal: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 117-127, 2010