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Alzheimer's Beta‐Secretase in Health and Disease

The neuritic plaques of Alzheimer's Disease (AD) are comprised of extracellular deposits of amyloid‐β (Aβ) peptides surrounded by dystrophic neurites, reactive astrocytes, and microglia. The Aβ peptides are derived from the sequential processing of amyloid‐β precursor protein (APP) by the activities of two enzymes termed, β‐ and γ‐secretase. The identification of β‐site APP cleaving enzyme 1 (BACE1) as the long sought β‐secretase required for the cleavage of APP to generate Aβ stimulated intense drug discovery research programs to identify pharmacological inhibitors of β‐secretase for the treatment of AD. Recent identification of important signaling pathways impacted by BACE1 raise concerns regarding the potential mechanism‐based toxicities associated with pharmacological inhibition of this aspartyl protease. For example, our recent discovery that BACE1 is critical for cognitive, emotional and synaptic functions raised concerns regarding mechanism‐based side effects associated with pharmacological inhibition of BACE1. Moreover, recent studies indicate that BACE1, acting through the neuregulin 1 (NRG1) signaling pathway, is required for proper myelination of central and peripheral axons. However, it is not known whether these alterations are restricted to development. To determine the impact of deletion of BACE1 during adulthood and aging as well as for clarifying mechanisms of clearance and repair from Aβ‐induced toxic effects, we generated and characterized an inducible BACE1 transgenic mouse model in which BACE1 expression is temporally and spatially controlled (using a “tet‐off” regulatory system). Results derived from these studies will have important implications for development of rational therapy to attenuate Aβ amyloidosis in AD.