Alterations in brain cholesterol metabolism in the APPSLxPS1mut mouse, a model for Alzheimer's disease.
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.
Vanmierlo
Tim
T
Department of Neuroscience, Maastricht University, Maastricht, The Netherlands.
Bloks
Vincent W
VW
van Vark-van der Zee
Leonie C
LC
Rutten
Kris
K
Kerksiek
Anja
A
Friedrichs
Silvia
S
Sijbrands
Eric
E
Steinbusch
Harry W
HW
Kuipers
Folkert
F
Lütjohann
Dieter
D
Mulder
Monique
M
D000367:Age Factors; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D003897:Desmosterol / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics; D053764:Presenilin-1 / Q000096:biosynthesis / Q000235:genetics*
D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D003897:Desmosterol; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human