Toxicity of Dutch (E22Q) and Flemish (A21G) mutant amyloid beta proteins to human cerebral microvessel and aortic smooth muscle cells.

[hereditary cerebral hemorrhage with amyloidosis]

Cerebral amyloid angiopathy (CAA ) is characterized by the deposition of amyloid beta protein (Abeta ) in cortical and leptomeningeal vessels of patients with Alzheimer 's disease and hereditary cerebral hemorrhage with amyloidosis , Dutch type . Smooth muscle cells (SMC ) from cerebral microvessels (MV ) are of particular interest as a site of Abeta-related injury because CAA is much more pronounced in the tunica media of cortical arterioles than meningeal arteries . Patients carrying point mutations at residues 22 (E 22 Q ) and 21 (A 21 G ) of Abeta show severe CAA with various degrees of brain parenchymal Abeta deposition . The purpose of this study was to investigate the effects of 2 mutant E 22 Q - and A 21 G-Abeta peptides on MV and aortic SMC . MERHODS : SMC were isolated from human cerebral MV and aorta . Cell morphology , viability , and proliferation as parameters of Abeta toxicity were investigated after 3 days of peptide treatment by trypan blue exclusion and [(3 )H ]thymidine incorporation .E 22 Q-Abeta induced significant decreased cellular proliferation and viability , as well as obvious degeneration of both MV and aortic SMC . A 21 G-Abeta and wild-type Abeta did not cause significant toxicity , as judged by cell morphology , viability , or cell proliferation , on either type of SMC .E 22 Q-Abeta induced greater toxicity in all parameters than A 21 G-Abeta and wild-type Abeta with respect to both MV and aortic SMC . A 21 G-Abeta did not show a significant toxic effect on MV and aortic SMC . This differential effect may be linked to cell type -specific processing and metabolism of mutant forms of Abeta . Mutations in amyloid precursor protein may lead to CAA by different pathogenetic mechanisms or share an unknown property that distinguishes them from wild-type Abeta .

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hereditary cerebral hemorrhage with amyloidosis

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