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Alzheimer’s disease (AD) is characterized by the extracellular deposition of the b-amyloid protein (Ab). Ab is a fragment of a much larger precursor protein, the amyloid precursor protein (APP). Sequential proteolytic cleavage of APP by b-secretase and g-secretase liberates Ab from APP. The aspartyl protease BACE1 (b-site APP-cleaving enzyme 1) catalyses the rate-limiting step in the production of Ab, 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.

Item Type:	Refereed Article
Keywords:	Alzheimer’s disease, amyloid, beta-secretase, beta-site APP cleaving enzyme (BACE), protease, therapy
Research Division:	Biomedical and Clinical Sciences
Research Group:	Neurosciences
Research Field:	Neurosciences not elsewhere classified
Objective Division:	Health
Objective Group:	Clinical health
Objective Field:	Clinical health not elsewhere classified
UTAS Author:	Klaver, DW (Mr David Klaver)
UTAS Author:	Cui, H (Mr Hao Cui)
UTAS Author:	Hung, AC (Dr Amos Hung)
UTAS Author:	Gasperini, R (Dr Rob Gasperini)
UTAS Author:	Foa, L (Professor Lisa Foa)
UTAS Author:	Small, DH (Professor David Small)
ID Code:	65156
Year Published:	2010
Web of Science® Times Cited:	31
Deposited By:	Menzies Institute for Medical Research
Deposited On:	2010-10-07
Last Modified:	2013-02-18
Downloads:	7 View Download Statistics