Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions
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David W. Klaver
Abstract
Alzheimer's disease (AD) is characterized by the extracellular deposition of the β-amyloid protein (Aβ). Aβ is a fragment of a much larger precursor protein, the amyloid precursor protein (APP). Sequential proteolytic cleavage of APP by β-secretase and γ-secretase liberates Aβ from APP. The aspartyl protease BACE1 (β-site APP-cleaving enzyme 1) catalyses the rate-limiting step in the production of Aβ, and as such it is considered to be a major target for drug development in Alzheimer's disease. However, the development of a BACE1 inhibitor therapy is problematic for two reasons. First, BACE1 has been found to have important physiological roles. Therefore, inhibition of the enzyme could have toxic consequences. Second, the active site of BACE1 is relatively large, and many of the bulky compounds that are needed to inhibit BACE1 activity are unlikely to cross the blood-brain barrier. This review focuses on the structure BACE1, current therapeutic strategies based on developing active-site inhibitors, and new approaches to therapy involving targeting the expression or post-translational regulation of BACE1.
©2010 by Walter de Gruyter Berlin New York
Articles in the same Issue
- Guest Editorial
- Highlight: The Biology of Proteolytic Systems
- Highlight: 6th General Meeting of the International Proteolysis Society
- Structure, mechanism and inhibition of γ-secretase and presenilin-like proteases
- Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions
- Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease
- Proteases in lymphocyte killer function: redundancy, polymorphism and questions remaining
- Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer
- Proteolysis of platelet receptors in humans and other species
- Blunting the knife: development of vaccines targeting digestive proteases of blood-feeding helminth parasites
- Impaired turnover of autophagolysosomes in cathepsin L deficiency
- Nuclear cysteine cathepsin variants in thyroid carcinoma cells
- Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer
- Cathepsin E enhances anticancer activity of doxorubicin on human prostate cancer cells showing resistance to TRAIL-mediated apoptosis
- Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8)
- Molecular contortionism – on the physical limits of serpin ‘loop-sheet’ polymers
- The substrate specificity profile of human granzyme A
- Use of granzyme B-based fluorescent protein reporters to monitor granzyme distribution and granule integrity in live cells
Articles in the same Issue
- Guest Editorial
- Highlight: The Biology of Proteolytic Systems
- Highlight: 6th General Meeting of the International Proteolysis Society
- Structure, mechanism and inhibition of γ-secretase and presenilin-like proteases
- Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions
- Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease
- Proteases in lymphocyte killer function: redundancy, polymorphism and questions remaining
- Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer
- Proteolysis of platelet receptors in humans and other species
- Blunting the knife: development of vaccines targeting digestive proteases of blood-feeding helminth parasites
- Impaired turnover of autophagolysosomes in cathepsin L deficiency
- Nuclear cysteine cathepsin variants in thyroid carcinoma cells
- Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer
- Cathepsin E enhances anticancer activity of doxorubicin on human prostate cancer cells showing resistance to TRAIL-mediated apoptosis
- Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8)
- Molecular contortionism – on the physical limits of serpin ‘loop-sheet’ polymers
- The substrate specificity profile of human granzyme A
- Use of granzyme B-based fluorescent protein reporters to monitor granzyme distribution and granule integrity in live cells
