One of the neuropathological hallmarks of Alzheimer’s disease (AD) is the
presence of brain senile plaques made up principally of aggregated amyloid beta (Aβ)
peptides. Aβ is produced during the consecutive proteolysis of the transmembrane
amyloid precursor protein (APP) by β- and γ-secretases. Genetic and pharmacological
manipulations have demonstrated the major β -secretase in AD that makes the initial
cleavage required for synthesis of Aβ is the beta-site APP-cleaving enzyme 1 (BACE1).
It is therefore very tempting to consider inhibiting BACE1 as a potential AD therapeutic
intervention. Here, we review the current knowledge and the molecular and
physiological challenges associated with BACE1 inhibition. We also propose
alternatives to the direct targeting of CNS BACE1 to prevent AD, as well as methods to
measure the therapeutic efficacy of BACE1 inhibition.
Keywords: Amyloid, Alzheimer’s, APP, BACE1, bapineuzumab, beta-secretase,
blood brain barrier, central nervous system, clinical trial, design, down syndrome,
gamma-secretase, immunotherapy, inhibition, modulation, optimization, periphery,
peptidomimetic, solanezumab, trafficking.
