4-hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer's disease

The amyloid beta -peptide (A beta) is a 4-kDa species derived from the amyl oid precursor protein, which accumulates in the brains of patients with Alz heimer's disease. Although we lack full understanding of the etiology and p athogenesis of selective neuron death, considerable data do imply roles for both the toxic A beta and increased oxidative stress. Another significant observation is the accumulation of abnormal, ubiquitin-conjugated proteins in affected neurons, suggesting dysfunction of the proteasome proteolytic s ystem in these cells. Recent reports have indicated that A beta can bind an d inhibit the proteasome, the major cytoslic protease for degrading damaged and ubiquitin-conjugated proteins. Earlier results from our laboratory sho wed that moderately oxidized proteins are preferentially recognized and deg raded by the proteasome; however, severely oxidized proteins cannot be easi ly degraded and, instead, inhibit the proteasome. We hypothesized that oxid atively modified A beta might have a stronger (or weaker) inhibitory effect on the proteasome than does native hp. We therefore also investigated the proteasome inhibitory action of A beta (1-40) (a peptide comprising the fir st 40 residues of A beta) modified by the intracellular oxidant hydrogen pe roxide, and by the lipid peroxidation product 4-hydroxynonenal (HNE). H2O2 modification of A beta (1-40) generates a progressively poorer inhibitor of the purified human 20S proteasome. In contrast, HNE modification of A beta (1-40) generates a progressively more selective and efficient inhibitor of the degradation of fluorogenic peptides and oxidized protein substrates by human 20S proteasome. This interaction may contribute to certain pathologi cal manifestations of Alzheimer's disease.