The membrane protein β-site APP-cleaving enzyme 1 (BACE1)5
is responsible for the β cleavage of the amyloid precursor protein (APP). The cleavage, which has been linked to the pathogenesis of Alzheimer disease (AD), results in the generation of a small APP fragment (commonly referred to as C99) acting as the immediate substrate for γ secretase (1
). The sequential β/γ processing of APP results into two small fragments, the amyloid β-peptide (Aβ), and the APP intracellular domain (AICD). Both have neurotoxic properties and both have been linked to the pathogenesis of AD (2
). Importantly, BACE1 acts as the rate-limiting enzyme. As a result, genetic disruption of BACE1 in the mouse abolishes both β and γ cleavage of APP and prevents AD neuropathology (10
). Therefore, mechanisms that regulate levels and/or activity of BACE1 could serve for therapeutic purposes. Unfortunately, biochemical design of BACE1 inhibitors has proven to be challenging due to the rather large size of the catalytic pocket of the enzyme (12
). Therefore, approaches that affect expression levels rather than catalytic activity of BACE1 are being actively sought.
We recently reported that nascent BACE1 is transiently acetylated in the lumen of the endoplasmic reticulum (ER) (13
) by two ER-based acetyl-CoA:lysine acetyltransferases, which we named ATase1 (also known as camello-like 2 and N
-acetyltransferase 8B) and ATase2 (also known as camello-like 1 and N
-acetyltransferase 8) (14
). The Nϵ
-lysine acetylation regulates the ability of nascent BACE1 to complete maturation. In fact, the acetylated intermediates of the nascent protein are able to reach the Golgi apparatus and complete maturation while the non-acetylated intermediates are retained and degraded in the ER Golgi intermediate compartment (ERGIC) (13
). Ex vivo
studies show that the levels of BACE1 are tightly regulated by the ATases. Specifically, up-regulation of ATase1 and ATase2 increases the levels of BACE1 and the generation of Aβ while siRNA-mediated down-regulation of either transferase achieves the opposite effects (14
Here, we report that both acetyltransferases are expressed in neurons and glial cells, and are up-regulated in the brain of AD patients. We also report the identification of novel biochemical inhibitors of ATase1 and ATase2 that significantly reduce the levels of BACE1 and the generation of Aβ in cellular systems. The biochemical properties of first and second generation compounds as well as mechanisms of inhibition are also described.