Alzheimer A beta neurotoxicity: promotion by antichymotrypsin, ApoE4; inhibition by A beta-related peptides.
Two inflammation-associated proteins found in the Alzheimer amyloid deposits-alpha 1-antichymotrypsin (ACT) and apolipoprotein E4 (apoE4)-have been shown to be genetic risk factors for the development of Alzheimer's disease and to promote the polymerization of the A beta peptide into amyloid filaments in vitro. In the present study, we show that ACT and apoE4 increase the neurotoxicity of the A beta peptide in parallel with their promotion of filament formation. Preincubation of ACT or apoE4 with small A beta-related peptides, or of apoE4 with apoE2, abrogated their subsequent ability to promote both the formation and the neurotoxicity of A beta filaments. These results indicate that ACT and apoE4 may play a stimulatory role in the formation of neurotoxic amyloid in Alzheimer's disease, and that their amyloid promoting activity can be blocked by inhibitory peptides.
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
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Brewer
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Potter
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000633:toxicity*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000494:pharmacology*; D002478:Cells, Cultured; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D006801:Humans; D008854:Microscopy, Electron; D018832:Molecular Chaperones; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010455:Peptides / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D000514:alpha 1-Antichymotrypsin / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D005904:Glial Fibrillary Acidic Protein; D018832:Molecular Chaperones; D009498:Neurotoxins; D010455:Peptides; D015842:Serine Proteinase Inhibitors; D000514:alpha 1-Antichymotrypsin