BACE1: More than just a β‐secretase

Abstract

Summary β‐site amyloid precursor protein cleaving enzyme‐1 (BACE1) research has historically focused on its actions as the β‐secretase responsible for the production of β‐amyloid beta, observed in Alzheimer's disease. Although the greatest expression of BACE1 is found in the brain, BACE1 mRNA and protein is also found in many cell types including pancreatic β‐cells, adipocytes, hepatocytes, and vascular cells. Pathologically elevated BACE1 expression in these cells has been implicated in the development of metabolic diseases, including type 2 diabetes, obesity, and cardiovascular disease. In this review, we examine key questions surrounding the BACE1 literature, including how is BACE1 regulated and how dysregulation may occur in disease, and understand how BACE1 regulates metabolism via cleavage of a myriad of substrates. The phenotype of the BACE1 knockout mice models, including reduced weight gain, increased energy expenditure, and enhanced leptin signaling, proposes a physiological role of BACE1 in regulating energy metabolism and homeostasis. Taken together with the weight loss observed with BACE1 inhibitors in clinical trials, these data highlight a novel role for BACE1 in regulation of metabolic physiology. Finally, this review aims to examine the possibility that BACE1 inhibitors could provide a innovative treatment for obesity and its comorbidities.

Amylin and Secretases in the Pathology and Treatment of Alzheimer’s Disease

“…Table 1 outlines the current status of clinical trials among these agents by targeting secretase and amylin [ 67 , 110 , 120 , 121 , 122 , 123 , 126 , 150 ]. Moreover, the findings of this review with regard to α-secretase activators, β-secretase inhibitors, γ-secretase inhibitors, and amylin agonists align with the findings of previous reviews but also build upon with recent evidence on small peptide therapeutics as well [ 27 , 72 , 149 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 ]. This is encouraging given the current development of newer of AD therapeutics outside of small peptides.…”

Potential therapeutic effects and pharmacological evidence of sinomenine in central nervous system disorders

“…In addition to AchE, βsecretase 1 (BACE1) is another molecule that may mediate the pathogenesis of AD. It is responsible for the proteolytic processing of the amyloid precursor molecule and the formation of Aβ fragments (Taylor et al, 2022). Administration of sinomenine can suppress the increase in BACE1 activity induced by trimethyltin in rat hippocampal tissue (Figure 3; Table 2), suggesting that inhibition of BACE1 may be also a possible mechanism for the anti-AD effect of sinomenine (Rostami et al, 2022).…”

Role of Natural Compounds and Target Enzymes in the Treatment of Alzheimer’s Disease

“…It claimed that extracellular amyloid deposits are the primary cause of AD [55]. β-secretase (BACE1) was found to be responsible for the creation of β-amyloid (Aβ) observed in AD [56]. Aβ is a type I transmembrane protein with a large extracellular domain and a short cytoplasmic portion that is generated from an amyloid precursor protein (APP).…”