Abstract
Beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a key drug target against Alzheimer’s Disease however, due to its promiscuous proteolytic activity, little is known about its physiological functions. Previous studies have analysed BACE1 cleavage products to examine BACE1 interactions and determine substrates, but these studies cannot establish non-enzymatic (and potentially functional) associations. This study used the biotin identification proximity assay to establish the BACE1 interactome in healthy neuronal cells and identified interactions involved in BACE1 trafficking, post-translational modification and substrates. Furthermore, this method has identified a putative novel role for BACE1 in sex hormone signalling and haem regulation through interaction with the progesterone receptor membrane component 2 (PGRC2). Data are available via ProteomeXchange with identifier PXD021464.
Highlights
One of the first pathological markers in Alzheimer’s Disease (AD) is increased production of neurotoxic amyloid beta (Aβ) peptides
Aβ is produced from sequential cleavage of the amyloid precursor protein (APP) and aggregates within the brain leading to the hallmark amyloid plaque deposits that are used as a marker for AD diagnosis [1]
Whilst APP processing occurs in healthy and diseased individuals, it is thought that changes in the initial cleavage step of APP determines whether the toxic forms of Aβ are produced
Summary
One of the first pathological markers in Alzheimer’s Disease (AD) is increased production of neurotoxic amyloid beta (Aβ) peptides. Many studies have used secretome analysis to identify fragments of putative BACE1 substrates leading to a library of plausible and in some cases independently validated protein interactions and suggesting that BACE1 substrate targeting is highly non-specific [4,5,6,7,8,9,10] Whilst this provides valuable information into the role of BACE1 as an aspartyl protease, there is evidence indicating that BACE1 may have additional, alternative non-enzymatic roles within the brain such as acting as a putative interaction partner of various post- and pre-synaptic neuronal voltage-gated potassium channels, resulting in modifications of their expression and function [11,12].
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