Toxicity of Dutch (E22Q) and Flemish (A21G) mutant amyloid beta proteins to human cerebral microvessel and aortic smooth muscle cells.
OBJECTIVE
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 (E22Q) and 21 (A21G) 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 E22Q- and A21G-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.


RESULTS
E22Q-Abeta induced significant decreased cellular proliferation and viability, as well as obvious degeneration of both MV and aortic SMC. A21G-Abeta and wild-type Abeta did not cause significant toxicity, as judged by cell morphology, viability, or cell proliferation, on either type of SMC.


CONCLUSIONS
E22Q-Abeta induced greater toxicity in all parameters than A21G-Abeta and wild-type Abeta with respect to both MV and aortic SMC. A21G-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.
Wang
Z
Z
Department of Pathology and Laboratory Medicine, Neuropathology, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095-1732, USA.
Natté
R
R
Berliner
J A
JA
van Duinen
S G
SG
Vinters
H V
HV
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000098:blood supply; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008833:Microcirculation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology*; D009154:Mutation; D010455:Peptides / Q000235:genetics / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D010455:Peptides