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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

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

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)