β-amyloid (25-35) enhances lipid metabolism and protein ubiquitination in cultured neurons

We investigated the effect of beta-amyloid (A beta) (25-35), a cytotoxic fragment of A beta pepticle, on lipid metabolism and protein ubiquitination in cultured rat hippocampal neurons. After treatment with A beta under conditions leading to apoptotis, as assessed by caspase activity assay, the total cell mass of lipids changed following a biphasic behavior, with an increase that reached a maximum after 16 hr of treatment, followed by a decrease. The increase at 16 hr was 15.3% in the case of phospholipids and 103.0% in the case of gangliosides and was due to enhanced biosynthesis as confirmed by increase of radioactivity incorporation (phospholipids +52.0%, gangliosides +193.1%) in cells fed with tritiated palmitic acid. No change with respect to cholesterol was observed. Strikingly, under these conditions, the ubiquitination state of cell proteins strongly increased. These effects were not observed with the (35-25) reverse sequence pepticle. Similarly to A beta, lactacystin treatment increased lipid synthesis and protein ubiquitination; only lactacystin, and not A beta, induced a strong decrease of proteasome chimotrypsin activity. These results suggest that A beta enhances protein ubiquitination, without inhibiting proteasomal activity, and lipid synthesis. These results may shed new light on the mechanisms of A beta toxicity. (c) 2007 Wiley-Liss, Inc.