Inherited amino acid substitutions at position 21, 22, or 23 of amyloid ␤ (A␤) lead to presenile dementia or stroke. Insulin-degrading enzyme (IDE) can hydrolyze A␤ wild type, yet whether IDE is capable of degrading A␤ bearing pathogenic substitutions is not known. We studied the degradation of all of the published A␤ genetic variants by recombinant rat IDE (rIDE). Monomeric A␤ wild type, Flemish (A21G), Italian (E22K), and Iowa (D23N) variants were readily degraded by rIDE with a similar efficiency. However, proteolysis of A␤ Dutch (E22Q) and Arctic (E22G) was significantly lower as compared with A␤ wild type and the rest of the mutant peptides. In the case of A␤ Dutch, inefficient proteolysis was related to a high content of ␤ structure as assessed by circular dichroism. All of the A␤ variants were cleaved at Glu 3 -Phe 4 and Phe 4 -Arg 5 in addition to the previously described major sites within positions 13-15 and 18 -21. SDS-stable A␤ dimers were highly resistant to proteolysis by rIDE regardless of the variant, suggesting that IDE recognizes a conformation that is available for interaction only in monomeric A␤. These results raise the possibility that upregulation of IDE may promote the clearance of soluble A␤ in hereditary forms of A␤ diseases.The accumulation of amyloid ␤ peptide (A␤) 1 in the brain is a central process in a number of human neurodegenerative disorders that may be grouped as "amyloid ␤ diseases" (1). In Alzheimer's disease, A␤ is mainly found within senile plaques in the neurophil and vascular lesions, whereas in sporadic and hereditary amyloid angiopathies, A␤ deposits are mainly associated with cortical and leptomeningeal vessels leading to stroke or multi-infarct dementia. To a lesser extent, cerebral A␤ deposits are also present in normal aging (2). Autosomal dominant mutations in the amyloid ␤ precursor protein (A␤ PP) gene result in amino acid substitutions at position 21, 22, or 23 of A␤ sequence. Although these A␤ variants present with a primarily vascular deposition, they translate into different clinical phenotypes. In this regard, A␤ Arctic (E22G) and A␤ Iowa (D23N) are characterized by presenile dementia and A␤ Flemish (A21G) is associated with early onset dementia and cerebral hemorrhage, whereas A␤ Dutch (E22Q) and A␤ Italian (E22K) variants have a predominant vascular phenotype characterized by massive strokes (3-7). The underlying mechanism of aggregation and deposition in vivo may be strongly influenced by the type of amino acid substitution as well as the location of mutations in the A␤ peptide. In vitro studies have shown that A␤ E22Q and A␤ D23N form typical amyloid fibrils at a higher rate than wild-type A␤ and that A␤ E22G assembles into unique protofibrils that may be toxic to neurons (3, 8 -10). In the case of A␤ A21G, overproduction of the peptide may contribute as a pathogenic mechanism (11, 12). Regarding A␤ E22K, deposition seems not to be related with fibril formation rate, and yet this variant may be toxic to human cerebrovascular smooth muscle cells in cult...

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