Membrane cholesterol enrichment prevents Aβ-induced oxidative stress in Alzheimer's fibroblasts

Abstract

A growing body of evidence implicates low membrane cholesterol in the pathogenesis of Alzheimer's disease (AD). Here we show that Aβ42 soluble oligomers accumulate more slowly and in reduced amount at the plasma membranes of PS-1L392V and APPV717I fibroblasts from familial AD (FAD) patients enriched in cholesterol content than at the counterpart membranes. The Aβ42-induced production of reactive oxygen species (ROS) and the increase in membrane lipoperoxidation were also prevented by high membrane cholesterol, thus resulting in a higher resistance to amyloid toxicity with respect to control fibroblasts. On the other hand, the recruitment of amyloid assemblies to the plasma membrane of cholesterol-depleted fibroblasts was significantly increased, thus triggering an earlier and sharper production of ROS and a higher membrane oxidative injury. These results identify membrane cholesterol as being key to Aβ42 oligomer accumulation at the cell surfaces and to the following Aβ42-induced cell death in AD neurons.

Membrane lipid composition and its physicochemical properties define cell vulnerability to aberrant protein oligomers

“…The cholesterol content was assayed in cell membrane fractions as previously described (Pensalfini et al, 2011) using the sensitive fluorimetric Amplex Red Cholesterol Assay Kit by comparison with cholesterol reference values (0.05-1.0 mg) (Zhou et al, 1997). The distribution of membrane cholesterol was also investigated using confocal scanning microscopy and the fluorescent probe filipin as previously reported (Pensalfini et al, 2011).…”

“…The distribution of membrane cholesterol was also investigated using confocal scanning microscopy and the fluorescent probe filipin as previously reported (Pensalfini et al, 2011). The emitted fluorescence was detected after excitation at 355 nm using a confocal Leica TCS SP5 scanning microscope equipped with an argon laser source.…”

“…The effect of exposure to HypF-N aggregates on cell morphology was investigated by using Hoechst 33342 staining as previously described (Pensalfini et al, 2011). Cells exposed for 24 hours to either HypF-N oligomer (12 mM) or to 12 mM native monomeric HypF-N were stained with 20 mg/ml Hoechst 33342 dye for 15 minutes at 37˚C.…”

Translocation of cellular prion protein to non-lipid rafts protects human prion-mediated neuronal damage

“…This observation may support the idea that cholesterol may have a protective effect against neurodegenerative diseases. Accordingly, a recent study suggested that increasing membrane cholesterol contents prevents mitochondrial disruptions in Alzheimer's disease (19,24,25). The effect of cholesterol on PrPSc-mediated mitochondrial dysfunction however, has not been reported.…”

“…Published articles can be divided into those suggesting that cholesterol may hasten the onset of neurodegenerative disorders and those that, on the other hand, support the notion that cholesterol may play a protective role in neurodegenerative diseases (16,17,19). Some studies in particular suggest that statins, cholesterol-lowering drugs, prevent neurodegenerative diseases, including prion diseases and Alzheimer's, and decrease PrPSc formation (20,21).…”