Objectives: 

Altered lipid raft homeostasis has been claimed to be a critical player in the cellular deregulation leading to neuronal loss in Alzheimer's disease. Alterations in these microdomains affect amyloid precursor protein (APP) processing and neurotransmitter signalling, resulting in neurotoxic conditions. However, although changes in the lipid composition of cell membranes have been postulated to be involved in neuronal degeneration, the potential modifications of the lipid structure of lipid rafts in Alzheimer's disease remains unknown.

Materials: 

We used a lipidomic approach to determine the molecular composition of lipid rafts lipid matrix isolated from frontal cortex in APP/PS1 double transgenic mice. Male mice were aged up to 3, 6, 9 and 14 months. Also, in order to establish the physicochemical properties of lipid rafts we used steady-state fluorescence polarization spectroscopy.

Results: 

We show that frontal cortex lipid rafts undergo a time-dependent modification both in wild type (WT) and APP/PS1 double transgenic mice. This process, which we have called "lipid-raft aging", is part of the normal aging programme and is characterized by decreased cholesterol and sterol esters levels, augmented sphyngomyelin and saturated fatty acids contents, and increased phospholipid-to-cholesterol ratio. In APP/PS1 animals, changes were more dramatic and precocious than in WT mice, and they also affected other lipid classes (such as sulphatides) and essential long chain polyunsaturated fatty acids (mainly docosahexaenoic acid). Steady-state polarization analyses demonstrate that APP/PS1 animals exhibit more liquid-ordered lipid rafts and that this feature is mainly attributable to reduced unsaturation of phospholipids rather than to changes in cholesterol.

Conclusions: 

In summary, we demonstrate that aging is accompanied by alteration of physicochemical structure of lipid raft microdomains. This "lipid-raft aging" process, as a metaphenomenon, is considerably exacerbated by APP/PS1 genotype.