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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