Charge alterations of E22 enhance the pathogenic properties of the amyloid beta-protein.
Cerebral amyloid angiopathy (CAA) due to amyloid beta-protein (Abeta) is a key pathological feature of patients with Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D). The CAA in these disorders is characterized by deposition of Abeta in the smooth muscle cells within the cerebral vessel wall. Recently, a new mutation in Abeta, E22K, was identified in several Italian families that, like HCHWA-D, is associated with CAA and hemorrhagic stroke. These two similar disorders, stemming from amino acid substitutions at position 22 of Abeta, implicate the importance of this site in the pathology of HCHWA. Previously we showed that HCHWA-D Abeta(1-40) containing the E22Q substitution induces robust pathologic responses in cultured human cerebrovascular smooth muscle cells (HCSM cells), including highly elevated levels of cell-associated Abeta precursor (AbetaPP) and cell death. In the present study, a series of E22 mutant Abeta(1-40) peptides were synthesized, and their pathogenic properties toward cultured HCSM cells were evaluated. Quantitative fluorescence analyses showed that mutant Abeta(1-40) peptides either containing a loss of charge (E22Q and E22A) or a change of charge (E22K) bind to the surface of HCSM cells and form amyloid fibrils. Similarly, this same group of E22 mutant Abeta(1-40) peptides caused enhanced pathologic responses in HCSM cells. In contrast, wild-type E22 or the charge-preserving E22D Abeta(1-40) peptides were devoid of any of these pathogenic properties. These data suggest that a change or loss of charge at position 22 of Abeta enhances the pathogenic effects of the peptide toward HCSM cells and may contribute to the pathogenesis of the phenotypically related HCHWA disorders.
Melchor
J P
JP
Department of Medicine, State University of New York, Stony Brook 11794-8153, USA.
McVoy
L
L
Van Nostrand
W E
WE
D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation; D004594:Electrophysiology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)