TY - JOUR
T1 - Aggregation and catabolism of disease-associated intra-Aβ mutations
T2 - reduced proteolysis of AβA21G by neprilysin
AU - Betts, Vicki
AU - Leissring, Malcolm A.
AU - Dolios, Georgia
AU - Wang, Rong
AU - Selkoe, Dennis J.
AU - Walsh, Dominic M.
PY - 2008/9
Y1 - 2008/9
N2 - Five point mutations within the amyloid β-protein (Aβ) sequence of the APP gene are associated with hereditary diseases which are similar or identical to Alzheimer's disease and encode: the A21G (Flemish), E22G (Arctic), E22K (Italian), E22Q (Dutch) and the D23N (Iowa) amino acid substitutions. Although a substantial body of data exists on the effects of these mutations on Aβ production, whether or not intra-Aβ mutations alter degradation and how this relates to their aggregation state remain unclear. Here we report that the E22G, E22Q and the D23N substitutions significantly increase fibril nucleation and extension, whereas the E22K substitution exhibits only an increased rate of extension and the A21G substitution actually causes a decrease in the extension rate. These substantial differences in aggregation together with our observation that aggregated wild type Aβ(1-40) was much less well degraded than monomeric wild type Aβ(1-40), prompted us to assess whether or not disease-associated intra-Aβ mutations alter proteolysis independent of their effects on aggregation. Neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin play a major role in Aβ catabolism, therefore we compared the ability of these enzymes to degrade wild type and mutant monomeric Aβ peptides. Experiments investigating proteolysis revealed that all monomeric peptides are degraded similarly by IDE and plasmin, but that the Flemish peptide was degraded significantly more slowly by NEP than wild type Aβ or any of the other mutant peptides. This finding suggests that resistance to NEP-mediated proteolysis may underlie the pathogenicity associated with the A21G mutation.
AB - Five point mutations within the amyloid β-protein (Aβ) sequence of the APP gene are associated with hereditary diseases which are similar or identical to Alzheimer's disease and encode: the A21G (Flemish), E22G (Arctic), E22K (Italian), E22Q (Dutch) and the D23N (Iowa) amino acid substitutions. Although a substantial body of data exists on the effects of these mutations on Aβ production, whether or not intra-Aβ mutations alter degradation and how this relates to their aggregation state remain unclear. Here we report that the E22G, E22Q and the D23N substitutions significantly increase fibril nucleation and extension, whereas the E22K substitution exhibits only an increased rate of extension and the A21G substitution actually causes a decrease in the extension rate. These substantial differences in aggregation together with our observation that aggregated wild type Aβ(1-40) was much less well degraded than monomeric wild type Aβ(1-40), prompted us to assess whether or not disease-associated intra-Aβ mutations alter proteolysis independent of their effects on aggregation. Neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin play a major role in Aβ catabolism, therefore we compared the ability of these enzymes to degrade wild type and mutant monomeric Aβ peptides. Experiments investigating proteolysis revealed that all monomeric peptides are degraded similarly by IDE and plasmin, but that the Flemish peptide was degraded significantly more slowly by NEP than wild type Aβ or any of the other mutant peptides. This finding suggests that resistance to NEP-mediated proteolysis may underlie the pathogenicity associated with the A21G mutation.
KW - Aggregation
KW - Alzheimer's disease
KW - Amyloid beta-protein
KW - Degradation
KW - Insulin degrading enzyme
KW - Plasmin
UR - http://www.scopus.com/inward/record.url?scp=49549098365&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2008.06.001
DO - 10.1016/j.nbd.2008.06.001
M3 - Article
C2 - 18602473
AN - SCOPUS:49549098365
SN - 0969-9961
VL - 31
SP - 442
EP - 450
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 3
ER -