Merk & Co., Inc.

Xiao-Ping Shi

Daria Hazuda

Yueming Li

Ming-Tain Lai

Min Xu

Adam J Simon

Bruce Register

Elizabeth Chen Dodson

Guoxin Wu

Provided are methods of identifying inhibitors of &#x3b2;-secretase that employ modified &#x3b2;-secretase substrates. The modified &#x3b2;-secretase substrates have &#x3b2;-secretase cleavage sites that are altered from wild type. The amino acid sequences of the altered &#x3b2;-secretase cleavage sites contain different amino acids in at least one of the positions P2-P1-P1'-P2&#x2032; of the &#x3b2;-secretase cleavage site. Many of the modified &#x3b2;-secretase substrates are more efficient substrates for &#x3b2;-secretase than are corresponding substrates having wild-type sequences, that is, these modified substrates are more susceptible to enzymatic breakdown by &#x3b2;-secretase. Recombinant polynucleotide molecules encoding the modified &#x3b2;-secretase substrates are provided. Antibodies that recognize cleavage products of the modified &#x3b2;-secretase substrates are provided. Stable cell lines expressing the modified &#x3b2;-secretase substrates are provided. Transgenic animals expressing the modified &#x3b2;-secretase substrates are provided.

Assays using amyloid precursor proteins with modified &#x3b2;-secretase cleavage sites to monitor &#x3b2;-secretase activity

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Warrington, PA, United States of America

Xiao-Ping Shi