Enhanced pathologic properties of Dutch-type mutant amyloid beta-protein.

Abstract

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.

• Authors: J Davis, W E Van Nostrand
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 93 Issue 7 Pg. 2996-3000 (Apr 02 1996) ISSN: 0027-8424 [Print] United States
• PMID: 8610157 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amyloid beta-Peptides
• Peptide Fragments
• Glutamine
• Glutamic Acid

Topics

• Alzheimer Disease (genetics)
• Amyloid beta-Peptides (chemical synthesis, genetics, toxicity)
• Amyloidosis (genetics)
• Cell Survival (drug effects)
• Cells, Cultured
• Cerebral Hemorrhage (genetics)
• Glutamic Acid
• Glutamine
• Humans
• Kinetics
• Meninges (blood supply)
• Muscle, Smooth, Vascular (cytology, drug effects)
• Netherlands
• Peptide Fragments (chemical synthesis, toxicity)
• Point Mutation