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Structural membrane alterations in Alzheimer brains found to be associated with regional disease development; increased density of gangliosides GM1 and GM2 and loss of cholesterol in detergent-resistant membrane domains

Artikel i vetenskaplig tidskrift
Författare Marie Molander-Melin
Kaj Blennow
Nenad Bogdanovic
Birgitta Dellheden
Jan-Eric Månsson
Pam Fredman
Publicerad i J Neurochem
Volym 92
Nummer/häfte 1
Sidor 171-82
ISSN 0022-3042 (Print)
Publiceringsår 2005
Publicerad vid Institutionen för klinisk neurovetenskap, Sektionen för laborativ neurovetenskap
Sidor 171-82
Språk en
Länkar htttp://dx.doi.org/10.1111/j.1471-4...
Ämnesord Aged, Aged, 80 and over, Alzheimer Disease/metabolism/*pathology, Cerebral Cortex/chemistry/metabolism/*pathology, Cholesterol/*metabolism, Detergents, Female, Frontal Lobe/chemistry/metabolism/pathology, G(M2) Activator Protein/biosynthesis/*metabolism, Humans, Male, Membrane Lipids/isolation & purification/metabolism, Membrane Microdomains/*chemistry/*pathology/ultrastructure, Middle Aged, Sphingolipid Activator Proteins/biosynthesis/*metabolism, Temporal Lobe/chemistry/metabolism/pathology
Ämneskategorier Neurokemi

Sammanfattning

The formation of neurotoxic beta-amyloid fibrils in Alzheimer's disease (AD) is suggested to involve membrane rafts and to be promoted, in vitro, by enriched concentrations of gangliosides, particularly GM1, and the cholesterol therein. In our study, the presence of rafts and their content of the major membrane lipids and gangliosides in the temporal cortex, reflecting late stages of AD pathology, and the frontal cortex, presenting earlier stages, has been investigated. Whole tissue and isolated detergent-resistant membrane fractions (DRMs) were analysed from 10 AD and 10 age-matched control autopsy brains. DRMs from the frontal cortex of AD brains contained a significantly higher concentration (micromol/micromol glycerophospholipids), of ganglioside GM1 (22.3 +/- 4.6 compared to 10.3 +/- 6.4, p <0.001) and GM2 (2.5 +/- 1.0 compared to 0.55 +/- 0.3, p <0.001). Similar increases of these gangliosides were also seen in DRMs from the temporal cortex of AD brains, which, in addition, comprised significantly lower proportions of DRMs. Moreover, these remaining rafts were depleted in cholesterol (from 1.5 +/- 0.2 to 0.6 +/- 0.3 micromol/micromol glycerophospholipids, p <0.001). In summary, we found an increased proportion of GM1 and GM2 in DRMs, and accelerating plaque formation at an early stage, which may gradually lead to membrane raft disruptions and thereby affect cellular functions associated with the presence of such membrane domains.

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