In vivo inhibition of Abeta production by memapsin 2 (beta-secretase) inhibitors |
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Authors: | Chang Wan-Pin Koelsch Gerald Wong Stephen Downs Deborah Da Huining Weerasena Vajira Gordon Brian Devasamudram Thippeswamy Bilcer Geoffrey Ghosh Arun K Tang Jordan |
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Institution: | Protein Studies Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA. |
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Abstract: | We have previously reported structure-based design of memapsin 2 (beta-secretase) inhibitors with high potency. Here we show that two such inhibitors covalently linked to a "carrier peptide" penetrated the plasma membrane in cultured cells and inhibited the production of beta-amyloid (Abeta). Intraperitoneal injection of the conjugated inhibitors in transgenic Alzheimer's mice (Tg2576) resulted in a significant decrease of Abeta level in the plasma and brain. These observations verified that memapsin 2 is a therapeutic target for Abeta reduction and also establish that transgenic mice are suitable in vivo models for the study of memapsin 2 inhibition. |
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Keywords: | Alzheimer's disease amyloid-β β-secretase inhibition mouse model |
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