β-secretase: Physiological role and target validation

Over the past several years, significant advances have been made towards our understanding of the physiological role of BACE1 and APP signaling pathway. Moreover, target validation studies indicate BACE1 to be a high priority anti-amyloid therapeutic target for the treatment of AD. However, inhibition of BACE1 activity may not be completely free of mechanism-based consequences related to possible roles of BACE1-dependent APP/AICD signaling in cognitive functions. It is anticipated that novel mechanism-based treatments such as BACE1 inhibitors will become available in the future. Therefore, it will be critical to understand some of the BACE1/APP mechanisms that influence cognition and emotional circuits in the CNS. BACE1 conditional knockout mouse models will be invaluable for clarifying whether cognitive deficits seen in BACE1 ^-/- mice are related to development or to aging, and whether BACE1 is involved directly in memory formation, as well as for evaluating to what extent Aβ peptide associated synaptic abnormalities are reversible following reductions of BACE1 activity. Finally, studies summarized in this review emphasize the pivotal roles that BACE1 plays in both health and disease, findings that are pertinent to the development of effective and safe anti-amyloid therapies for the treatment of this devastating disease of the elderly.