Comparison of the aggregation properties, secondary structure and apoptotic effects of wild-type, Flemish and Dutch N-terminally truncated amyloid beta peptides

Citation
N. Demeester et al., Comparison of the aggregation properties, secondary structure and apoptotic effects of wild-type, Flemish and Dutch N-terminally truncated amyloid beta peptides, EUR J NEURO, 13(11), 2001, pp. 2015-2024
Citations number
41
Categorie Soggetti
Neurosciences & Behavoir
Journal title
EUROPEAN JOURNAL OF NEUROSCIENCE
ISSN journal
0953816X → ACNP
Volume
13
Issue
11
Year of publication
2001
Pages
2015 - 2024
Database
ISI
SICI code
0953-816X(200106)13:11<2015:COTAPS>2.0.ZU;2-H
Abstract
The Dutch (E22Q) and Flemish (A21G) mutations in the beta APP region of the amyloid precursor protein (APP) are associated with familial forms of Alzh eimer dementia. However, patients with these mutations express substantiall y different clinical phenotypes. Therefore, secondary structure and cytotox ic effects of the three A beta (12-42) variants [wild-type (WT), Dutch and Flemish] were tested. At a concentration of 5 muM the aggregation of these peptides followed the order: A beta (1-42) WT > A beta (12-42) WT > A beta (12-42) Flemish > A beta (12-42) Dutch. The stability of the secondary stru cture of these peptides upon decreasing the trifluoroethanol (TFE) concentr ation in the buffer was followed by circular dichroism measurements. WT pep tides progressively lost their alpha -helical structure; this change occurr ed faster for both the Flemish and Dutch peptides, and at higher percentage s of TFE in the buffer, and was accompanied by an increase in beta -sheet a nd random coil content. Apoptosis was induced in neuronal cells by the A be ta (12-42) WT and Flemish peptides at concentrations as low as 1-5 muM, as evidenced by propidium iodide (PI) staining, DNA laddering and caspase-3 ac tivity measurements, Even when longer incubation times and higher peptide c oncentrations were applied the N-truncated Dutch peptide did not induce apo ptosis. Apoptosis induced by the full length A beta (1-42) peptide was weak er than that induced by its N-truncated variant. These data suggest that N- truncation enhanced the cytotoxic effects of A beta WT and Flemish peptides , which may play a role in the accelerated progression of dementia.