期刊
NEUROCHEMICAL RESEARCH
卷 34, 期 6, 页码 1167-1182出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11064-008-9893-4
关键词
BACE; Cholesterol; Seladin-1; Plasmin; Proteoliposomes; Sterols; GM1
资金
- Swiss National Science Foundation [3200BO-112616, 451NF40-111381]
- University of Zurich
- Swiss Academy of Medical Sciences
- Hermann Klaus
- Hartmann Muller
- Novartis Foundations
- Regione Piemonte to MDL
- US National Institutes of Health to FLH [NINDS R01 NS046006]
- EU [LSHM-CT-2003-503330, DFGSFB6027]
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 A beta 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.
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