Enhanced pathologic properties of Dutch-type mutant amyloid beta-protein.
Cerebrovascular amyloid beta-protein (Abeta) deposition is a pathological feature of several related disorders including Alzheimer disease and hereditary cerebral hemorrhage with amyloidosis Dutch-type (HCHWA-D). HCHWA-D is caused by a point mutation in the gene that encodes the Abeta precursor and results in a Glu --> Gln substitution at position 22 of Abeta. In comparison to Alzheimer disease, the cerebrovascular Abeta deposition in HCHWA-D is generally more severe, often resulting in intracerebral hemorrhage when patients reach 50 years of age. We recently reported that Abeta(1-42), but not the shorter Abeta(1-40) induces pathologic responses in cultured human leptomeningeal smooth muscle cells including cellular degeneration that is accompanied by a marked increase in the levels of cellular Abeta precursor and soluble Abeta peptide. In the present study, we show that the HCHWA-D mutation converts the normally nonpathologic Abeta(1-40) into a highly pathologic form of the peptide for cultured human leptomeningeal smooth muscle cells. These findings suggest that these altered functional properties of HCHWA-D mutated Abeta may contribute to the early and often severe cerebrovascular pathology that is the hallmark of this disorder.
Davis
J
J
Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine 92717-4025, USA.
Van Nostrand
W E
WE
D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000235:genetics / Q000633:toxicity*; D000686:Amyloidosis / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000235:genetics; D018698:Glutamic Acid; D005973:Glutamine; D006801:Humans; D007700:Kinetics; D008578:Meninges / Q000098:blood supply; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009426:Netherlands; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000633:toxicity*; D017354:Point Mutation
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D005973:Glutamine; D018698:Glutamic Acid