Common BACE2 Polymorphisms are Associated with Altered Risk for Alzheimer’s Disease and CSF Amyloid Biomarkers in APOE ε4 Non-Carriers

Abstract

It was recently suggested that beta-site amyloid precursor protein (APP)-cleaving enzyme 2 (BACE2) functions as an amyloid beta (Aβ)-degrading enzyme; in addition to its better understood role as an APP secretase. Due to this finding we sought to understand the possible genetic risk contributed by the BACE2 locus to the development of late-onset Alzheimer’s disease (AD). In this study, we report that common single nucleotide polymorphism (SNP) variation in BACE2 is associated with altered AD risk in apolipoprotein E gene (APOE) epsilon 4 variant (ε4) non-carriers. In addition, in ε4 non-carriers diagnosed with AD or mild cognitive impairment (MCI), SNPs within the BACE2 locus are associated with cerebrospinal fluid (CSF) levels of Aβ1-42. Further, SNP variants in BACE2 are also associated with BACE2 RNA expression levels suggesting a potential mechanism for the CSF Aβ1-42 findings. Lastly, overexpression of BACE2 in vitro resulted in decreased Aβ1-40 and Aβ1-42 fragments in a cell line model of Aβ production. These findings suggest that genetic variation at the BACE2 locus modifies AD risk for those individuals who don’t carry the ε4 variant of APOE. Further, our data indicate that the biological mechanism associated with this altered risk is linked to amyloid generation or clearance possibly through BACE2 expression changes.

BACE2 degradation is mediated by both the proteasome and lysosome pathways

“…In conclusion, we found that BACE2 is degraded by both the proteasome and the lysosome pathways in both neuronal cells and non-neuronal cells at endogenous level or in transient overexpression system, indicating that BACE2 degradation by both the proteasome and lysosome pathways is a common feature of BACE2. Moreover, the impairment of the proteasome pathway and the lysosome pathway in AD might lead to BACE2 dysregulation in neurons, contributing to the pathogenesis of AD [10]. This study not only advances our understanding of the regulation of BACE2 but also provides a potential mechanism of its dysregulation in AD.…”

“…For example, BACE2 haplotype associates with AD, while SNPs in BACE2 (e.g., rs2252576, rs2837990, rs7281733) predispose to early onset of AD in patients with Down syndrome [8,9]. Recently, the association between a number of SNPs in BACE2 and AD was detected in APOE ε4 non-carriers, which might be mediated by altered BACE2 expression-mediated Aβ generation and clearance [10]. It indicates that dysregulation of BACE2 might contribute to the pathogenesis AD.…”

The emerging role of β-secretases in cancer

“…Further, it would be interesting to define which are the mechanisms that drive the over-expression of BACE2 in different cancer subtypes looking at SNP (single nucleotide polymorphism) and CNV (copy number variation) as it was reported for patients affected by Alzheimer’s disease [ 79 ].…”

Role of Neuron and Glia in Alzheimer’s Disease and Associated Vascular Dysfunction

“…APP, PSEN1 or PSEN2 trigger familial AD, together with cholesterol and lipoprotein dysfunction, altered peripheral lipid metabolism and polymorphic gene expression (Dai et al, 2018 ; Huentelman et al, 2019 ). LRP1, that has a significant contribution in vascular dysfunctions (Ramanathan et al, 2015 ), modulates Aβ generation via altered regulation of proteases, growth factors and an eventual inflammation (Ashok et al, 2016 ; He et al, 2020b ).…”