Alzheimer's and oxidized cholesterol: Neighbors come together

Lipidomics Gateway (26 August 2009) [doi:10.1038/lipidmaps.2009.20]

An oxidized form of cholesterol alters membrane organization and might disrupt cellular function in Alzheimer's disease.

Alzheimer's disease is characterized by accumulation of the neurotoxic peptide β-amyloid. This peptide can oxidize cholesterol to form the oxysterol 7β-hydroxycholesterol ¹ (7β-OH). Although cholesterol in cell membranes brings neighboring phospholipid molecules closer together, by inducing a partial straightening of their acyl chains, the effect of 7β-OH on membrane organization is unknown. Now Steven Regen and colleagues report in the Journal of the American Chemical Society that the condensing effect of 7β-OH is enhanced compared to that of cholesterol. This produces a membrane reorganization that might help to explain the enigmatic etiology of Alzheimer's disease.

7β-hydroxycholesterol is produced by oxidation of cholesterol (top)

Glycerophospholipids, typically containing a cis-double bond in one of their hydrocarbon tails, pack more loosely in membranes than the longer, straighter sphingolipids, and exist in a liquid-disordered state, or phase. Lipid rafts are membrane microdomains that, by contrast, exist in a liquid-ordered (l_o ) phase, enriched in sterols and in the higher melting temperature phosphoglycerides and sphingolipids. Cholesterol promotes the lo phase through hydrophobic interactions with acyl chains and by their dehydration, driving their uncoiling and allowing closer packing of molecules. The uncoiling of the phospholipids also results in the local thickening of the membrane. Energetically, it is favorable for cholesterol and longer phospholipids to be immediate neighbors in a membrane, which in turn favors raft formation ² .

Both β-amyloid and its precursor protein APP produce 7β-OH, but the rate of production is much greater for the peptide ¹ . Nanomolar concentrations of 7β-OH are toxic to cultured neurons but the mechanism of cell death is not clear. Given the powerful membrane-ordering properties of cholesterol, Regen and colleagues wanted to know what effect the 7β oxidation has on membrane organization. To find out, they used a method called nearest-neighbor recognition (NNR) to quantify the effects of 7β-OH on lipid interactions in the l_o phase.

For NNR, two chosen lipid molecules (here a phospholipid and a sterol) are each converted into dimers linked with a disulfide bond, and are incorporated into liposomal membranes. When these molecules neighbor one another in the membrane, monomer units can swap partners through thiolate-disulfide exchange. The rate of exchange is quantified, and the value of a calculated equilibrium constant K indicates whether homo- or hetero-associations are favored, or whether the two lipid species mix freely within the membrane.

Before making the NNR measurements, the authors used a phase-sensitive fluorescent probe to show that the liposomes, containing 40 mol% sterol, were in the l_o phase and that this was not disrupted by incorporation of 7β-OH. In agreement with this, the K values of the NNR measurements all indicated that hetero-associations were favored whether cholesterol or 7β-OH was predominant. Nevertheless, K increased steadily as cholesterol was incrementally replaced by 7β-OH. In other words, 7β-OH in the membrane strengthens the interactions of phospholipids with sterols. The position of the extra hydroxyl of 7β-OH favors closer packing of the sterol with phospholipid acyl chains, and produces an even greater condensing effect on the membrane compared with cholesterol.

The biological implications of these findings are not yet clear, but could be significant. The change to K with increasing 7β-OH corresponds to a free energy more than sufficient to induce phase separation in a computer simulation, indicating that major changes to membrane structure could be produced. Even a modest excess of 7β-OH could locally thicken the membrane and make fewer high-melting lipids available to contiguous proteins, potentially disrupting signaling at lipid rafts. Whether this is a key factor in the cellular malfunction of Alzheimer's disease deserves further investigation.

Emma Leah