caa a22 4500 475845471 CHVBK 20180406123913.0 cr unu---uuuuu 170329e20001001xx s 000 0 eng 10.1007/PL00000660 doi (NATIONALLICENCE)springer-10.1007/PL00000660 4-Hydroxynonenal-modified amyloid-β peptide inhibits the proteasome: possible importance in Alzheimer's disease* [Elektronische Daten] [R. Shringarpure, T. Grune, N. Sitte, K. J. A. Davies*] Abstract.: The amyloid β-peptide (Aβ) is a 4-kDa species derived from the amyloid precursor protein, which accumulates in the brains of patients with Alzheimer's disease. Although we lack full understanding of the etiology and pathogenesis of selective neuron death, considerable data do imply roles for both the toxic Aβ and increased oxidative stress. Another significant observation is the accumulation of abnormal, ubiquitin-conjugated proteins in affected neurons, suggesting dysfunction of the proteasome proteolytic system in these cells. Recent reports have indicated that Aβ can bind and inhibit the proteasome, the major cytoslic protease for degrading damaged and ubiquitin-conjugated proteins. Earlier results from our laboratory showed that moderately oxidized proteins are preferentially recognized and degraded by the proteasome; however, severely oxidized proteins cannot be easily degraded and, instead, inhibit the proteasome. We hypothesized that oxidatively modified Aβ might have a stronger (or weaker) inhibitory effect on the proteasome than does native Aβ. We therefore also investigated the proteasome inhibitory action of Aβ 1-40 (a peptide comprising the first 40 residues of Aβ) modified by the intracellular oxidant hydrogen peroxide, and by the lipid peroxidation product 4-hydroxynonenal (HNE). H2O2 modification of Aβ 1-40 generates a progressively poorer inhibitor of the purified human 20S proteasome. In contrast, HNE modification of Aβ 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 pathological manifestations of Alzheimer's disease Birkhäuser Verlag Basel,, 2000 Key words. Amyloid beta peptide nationallicence Alzheimer's disease nationallicence oxidative stress nationallicence proteasome nationallicence proteolysis nationallicence protein degradation nationallicence protein oxidation nationallicence 4-hydroxynonenal nationallicence free radical nationallicence Shringarpure R. Ethel Percy Andrus Gerontology Center, and the Division of Molecular Biology, 3715 McClintock Avenue, University of Southern California, Los Angeles (California 90089-0191, USA), Fax + 213 740 6462, e-mail: kelvin@rcf.usc.edu, US aut Grune T. Ethel Percy Andrus Gerontology Center, and the Division of Molecular Biology, 3715 McClintock Avenue, University of Southern California, Los Angeles (California 90089-0191, USA), Fax + 213 740 6462, e-mail: kelvin@rcf.usc.edu, US aut Sitte N. Clinics of Physical Medicine and Rehabilitaion, Medical Faculty (Charite), Humboldt University, Berlin (Germany), DE aut Davies* K. J. A. Ethel Percy Andrus Gerontology Center, and the Division of Molecular Biology, 3715 McClintock Avenue, University of Southern California, Los Angeles (California 90089-0191, USA), Fax + 213 740 6462, e-mail: kelvin@rcf.usc.edu, US aut https://doi.org/10.1007/PL00000660 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/PL00000660 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Shringarpure R. Ethel Percy Andrus Gerontology Center, and the Division of Molecular Biology, 3715 McClintock Avenue, University of Southern California, Los Angeles (California 90089-0191, USA), Fax + 213 740 6462, e-mail: kelvin@rcf.usc.edu, US aut NATIONALLICENCE 700 1- Grune T. Ethel Percy Andrus Gerontology Center, and the Division of Molecular Biology, 3715 McClintock Avenue, University of Southern California, Los Angeles (California 90089-0191, USA), Fax + 213 740 6462, e-mail: kelvin@rcf.usc.edu, US aut NATIONALLICENCE 700 1- Sitte N. Clinics of Physical Medicine and Rehabilitaion, Medical Faculty (Charite), Humboldt University, Berlin (Germany), DE aut NATIONALLICENCE 700 1- Davies* K. J. A. Ethel Percy Andrus Gerontology Center, and the Division of Molecular Biology, 3715 McClintock Avenue, University of Southern California, Los Angeles (California 90089-0191, USA), Fax + 213 740 6462, e-mail: kelvin@rcf.usc.edu, US aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer