Inhibiting the generation of β-amyloid (Aβ) from the amyloid precursor
protein (APP) by targeting the protease BACE1, the Alzheimer’s disease β-secretase, is
a key strategy for the development of therapeutic compounds aimed at treating
Alzheimer’s disease. However, progress in developing biologically active inhibitors has
been slow. This is in part because BACE1 possesses a broad and open active site, which
cannot be effectively inhibited by small molecules capable of penetrating the bloodbrain
barrier. Therefore, there is a great interest in developing modulators of BACE1
activity that are not associated with active site inhibition, rather disrupting the
physiological function of the enzyme. This review will discuss the regulation of BACE1
transcriptional expression and modulation of activity by other cellular components, in
particular lipids, proteins that interact directly with BACE1, and ubiquitination, as well
as BACE1 immunotherapy. This review will also examine the potential of each of these
as therapeutic strategies for the treatment of AD.
