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.
Highlights
The amyloid (Aβ) hypothesis of Alzheimer’s disease (AD) has primarily been driven by the observation that genetic variability that alters amyloid precursor protein (APP) metabolism increases de position of Aβ1
Fluhrer et al demonstrated that the cleavage of APP via BACE2 results in production of soluble APP-α and reduced production of amyloidogenic species suggesting that APP metabolism by BACE2 acts in an opposing fashion to BACE1 in cells that express both enzymes[8]
Overexpression of BACE2 in a cell line that naturally produces Aβ peptides results in lower amounts of Aβ140 and Aβ1-42. Considered together, these data suggest that genetic variation at the BACE2 locus is associated with AD risk and that it may be functionally linked to altered Aβ processing
Summary
The amyloid (Aβ) hypothesis of Alzheimer’s disease (AD) has primarily been driven by the observation that genetic variability that alters amyloid precursor protein (APP) metabolism increases de position of Aβ1. SNPs within the BACE2 locus were associated with altered Alzheimer’s disease risk preferentially in APOE ε4 non-carriers. In individuals with diagnosed AD or MCI who do not carry an APOE ε4 allele, SNPs within BACE2 were associated with differential Aβ1-42 levels in the CSF.
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