title: Age-dependent increase in desmosterol restores DRM formation and membrane-related functions in cholesterol-free DHCR24-/- mice.
abstract: Cholesterol is a prominent modulator of the integrity and functional activity of physiological membranes and the most abundant sterol in the mammalian brain. DHCR24-knock-out mice lack cholesterol and accumulate desmosterol with age. Here we demonstrate that brain cholesterol deficiency in 3-week-old DHCR24(-/-) mice was associated with altered membrane composition including disrupted detergent-resistant membrane domain (DRM) structure. Furthermore, membrane-related functions differed extensively in the brains of these mice, resulting in lower plasmin activity, decreased beta-secretase activity and diminished Abeta generation. Age-dependent accumulation and integration of desmosterol in brain membranes of 16-week-old DHCR24(-/-) mice led to the formation of desmosterol-containing DRMs and rescued the observed membrane-related functional deficits. Our data provide evidence that an alternate sterol, desmosterol, can facilitate processes that are normally cholesterol-dependent including formation of DRMs from mouse brain extracts, membrane receptor ligand binding and activation, and regulation of membrane protein proteolytic activity. These data indicate that desmosterol can replace cholesterol in membrane-related functions in the DHCR24(-/-) mouse.
authors.affiliation: Division of Psychiatry Research, University of Zurich, Zurich, Switzerland. k.kuehnle@samw.ch
authors.forename: Katrin
authors.initials: K
authors.lastname: Kuehnle
authors.forename: Maria D
authors.initials: MD
authors.lastname: Ledesma
authors.forename: Lucie
authors.initials: L
authors.lastname: Kalvodova
authors.forename: Alicia E
authors.initials: AE
authors.lastname: Smith
authors.forename: Arames
authors.initials: A
authors.lastname: Crameri
authors.forename: Fabienne
authors.initials: F
authors.lastname: Skaanes-Brunner
authors.forename: Karin M
authors.initials: KM
authors.lastname: Thelen
authors.forename: Luka
authors.initials: L
authors.lastname: Kulic
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
authors.forename: Roger M
authors.initials: RM
authors.lastname: Nitsch
authors.forename: M Hasan
authors.initials: MH
authors.lastname: Mohajeri
mesh_terms: D000375:Aging / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D002784:Cholesterol / Q000172:deficiency; D003897:Desmosterol / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D021962:Membrane Microdomains / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding; D011510:Proteolipids / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008563:Membrane Lipids; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011510:Proteolipids; C020485:proteoliposomes; D003897:Desmosterol; D005677:G(M1) Ganglioside; D010958:Plasminogen; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499056:Dhcr24 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D005341:Fibrinolysin