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.
Ma
J
J
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Brewer
H B
HB
Potter
H
H
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