Age-dependent increase in desmosterol restores DRM formation and membrane-related functions in cholesterol-free DHCR24-/- mice.
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.
Kuehnle
Katrin
K
Division of Psychiatry Research, University of Zurich, Zurich, Switzerland. k.kuehnle@samw.ch
Ledesma
Maria D
MD
Kalvodova
Lucie
L
Smith
Alicia E
AE
Crameri
Arames
A
Skaanes-Brunner
Fabienne
F
Thelen
Karin M
KM
Kulic
Luka
L
Lütjohann
Dieter
D
Heppner
Frank L
FL
Nitsch
Roger M
RM
Mohajeri
M Hasan
MH
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
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