Physiological Functions of the β-Site Amyloid Precursor Protein Cleaving Enzyme 1 and 2

Abstract

BACE1 was discovered as the β-secretase for initiating the cleavage of amyloid precursor protein (APP) at the β-secretase site, while its close homology BACE2 cleaves APP within the β-amyloid (Aβ) domain region and shows distinct cleavage preferences in vivo. Inhibition of BACE1 proteolytic activity has been confirmed to decrease Aβ generation and amyloid deposition, and thus specific inhibition of BACE1 by small molecules is a current focus for Alzheimer’s disease therapy. While BACE1 inhibitors are being tested in advanced clinical trials, knowledge regarding the properties and physiological functions of BACE is highly important and this review summarizes advancements in BACE1 research over the past several years. We and others have shown that BACE1 is not only a critical enzyme for testing the “Amyloid Hypothesis” associated with Alzheimer’s pathogenesis, but also important for various functions such as axon growth and pathfinding, astrogenesis, neurogenesis, hyperexcitation, and synaptic plasticity. BACE2 appears to play different roles such as glucose homeostasis and pigmentation. This knowledge regarding BACE1 functions is critical for monitoring the safe use of BACE1 inhibitors in humans.

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

“…The proteolytic cut occurs within the extracellular or luminal juxtamembrane (membrane‐proximal) region or within the TM anchor of a membrane protein substrate. Cleavage sites within the juxtamembrane region are typically at a short distance of often 10 ‐ 35 amino acids from the TM segment, but more distant cleavage sites are possible and, in fact, the exact cleavage sites have only been determined for few shedding substrates (e.g., summarized for ADAMs and BACE1 in Caescu et al , ; Yan, ).…”

“…The proteolytic cut occurs within the extracellular or luminal juxtamembrane (membraneproximal) region or within the TM anchor of a membrane protein substrate. Cleavage sites within the juxtamembrane region are typically at a short distance of often 10 -35 amino acids from the TM segment, but more distant cleavage sites are possible and, in fact, the exact cleavage sites have only been determined for few shedding substrates (e.g., summarized for ADAMs and BACE1 in Caescu et al, 2009;Yan, 2017). Several other proteolytic events in cells, such as removal of a signal peptide by signal peptidase (Blobel & Dobberstein, 1975) and proteolytic cleavages by mitochondrial AAA proteases (Levytskyy et al, 2017), formally share similarities to ectodomain shedding, but will not be discussed in this review, as they occur either during protein biosynthesis but not on the mature protein (signal peptidase), or do not occur in the secretory or endocytic pathway (mitochondria).…”

Role of BACE1 in Alzheimer’s synaptic function

“…It has been shown that BACE1 is normally expressed in broad brain regions, with rich expression by hippocampal granule cells. BACE1 has been shown to play a critical role in synaptic development and plasticity through cleavage of its various substrates [51, 53, 54]. The effects of BACE1 on synaptic functions are likely to be through multiple mechanisms, as discussed below.

BACE1 deficiency alters synaptic plasticity in relation to APP cleavage: Long-term changes in the strength of synaptic transmission are the basis of memory formation.

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“Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain”

“…The ratio of 1-19/amyloidogenics was significantly higher in T21 lines from the isogenic model, compared to its disomic isogenic control, and compared to DupAPP, but it was unchanged in the other two unrelated DS iPSC lines (see also Supplementary Information for a more detailed explanation). As the proportions of BACE2-unrelated α-site cleavage products (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) were not different between T21 and isogenic D21 organoids (in any of the 3 experiments) ( Fig. 1a), it can be predicted that the increased presence of 1-19, 1-20 and 1-34 peptides in T21 contributes towards an overall increase in soluble peptides that are non-amyloidogenic.…”

“…BACE1 is the main β-secretase in the brain 9 , while the expression and function of its homologue BACE2 (encoded by a chromosome 21 gene) remain less clear 10,11 . At least 3 different activities of BACE2 were recorded with regards to APP processing: as an auxiliary β-secretase (proamyloidogenic), as a θ-secretase (degrading the β-CTF and preventing the formation of Aβ), and as Aβ-degrading protease (AβDP) (degrading synthetic Aβ-peptides at extremely acidic pH).…”