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

Cerebrovascular amyloid beta-protein (A beta) 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 A beta precursor and results in a Glu --> Gin substitution at position 22 of A beta, In comparison to Alzheimer disease, the cerebrovascular A beta deposition in HCHWA-D is generally more severe, often resulting in intracerebral hemorrhage when patients reach 50 years of age, We recently reported that A beta(1-42), but not the shorter A beta(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 A beta precursor and soluble A beta peptide, In the present study, we show that the HCHWA-D mutation converts the normally nonpathologic A beta(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 A beta may contribute to the early and often severe cerebrovascular pathology that is the hallmark of this disorder.