R. Shringarpure et al., 4-hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer's disease, CELL MOL L, 57(12), 2000, pp. 1802-1809
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.