Evidence for dimeric BACE-mediated APP processing

Jin, Shaobo; Agerman, Karin; Kolmodin, Karin; Gustafsson, Elin; Dahlqvist, Camilla; Juréus, Anders; Liu, Gang; Fälting, Johanna; Berg, Stefan von; Lundkvist, Johan; Lendahl, Urban

doi:10.1016/j.bbrc.2010.01.064

Cited by 22 publications

(15 citation statements)

References 17 publications

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“…Most importantly, the effects of BACE1 were non-proteolytic in nature, since they were reproduced by a proteolytically inactive BACE1 mutant. 102 Thus, the non-enzymatic interaction between BACE1 and the a-subunit of voltage-dependent ion channels first reported for Na v 1.2 (see above) seems to emerge as a more widely applicable mechanism through which BACE1 can influence neuronal excitability. Coimmunoprecipitation and proximity ligation assay served as independent means to confirm direct BACE1/KCNQ interaction (Fig.…”

Section: Direct Interaction and Kcnq Gatingmentioning

confidence: 96%

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

et al. 2016

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b-site APP-cleaving enzyme 1 (BACE1) has become infamous for its pivotal role in the pathogenesis of Alzheimer's disease (AD). Consequently, BACE1 represents a prime target in drug development. Despite its detrimental involvement in AD, it should be quite obvious that BACE1 is not primarily present in the brain to drive mental decline. In fact, additional functions have been identified. In this review, we focus on the regulation of ion channels, specifically voltage-gated sodium and KCNQ potassium channels, by BACE1. These studies provide evidence for a highly unexpected feature in the functional repertoire of BACE1. Although capable of cleaving accessory channel subunits, BACE1 exerts many of its physiologically significant effects through direct, non-enzymatic interactions with main channel subunits. We discuss how the underlying mechanisms can be conceived and develop scenarios how the regulation of ion conductances by BACE1 might shape electric activity in the intact and diseased brain and heart.

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Section: Direct Interaction and Kcnq Gatingmentioning

confidence: 96%

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

et al. 2016

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“…APP_VN (APP695 isoform), APPstop40_VN (aa 1–636, APP695 numbering), BACE1_VC, and mCherry were generously provided by Professor Subhojit Roy [36] (University of California, San Diego, USA). Human wild-type BACE1 construct was a kind gift from Dr. Shaobo Jin [37] (Karolinska Institutet, Sweden). The reading frames of all cloned constructs were confirmed by DNA sequencing.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of SNX3 Decreases Amyloid-β Peptide Production by Reducing Internalization of Amyloid Precursor Protein

Nigam

Brodin

2018

Neurodegener Dis

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Background: Sorting nexins (SNXs) have diverse functions in protein sorting and membrane trafficking. Recently, single-nucleotide polymorphisms in SNX3 were found to be associated with Alzheimer disease. However, it remains unknown whether SNX3 participates in amyloid (A)β peptide production. Objective: To examine the role of SNX3 in Aβ production and APP processing. Methods: The effect of increased expression of SNX3 was studied in HEK293T cells. Aβ peptides were measured by immunoassay. Protein-protein association was analyzed by a bimolecular fluorescence complementation (BiFC) assay. APP uptake was measured with an α-bungarotoxin-binding assay, and flow cytometry was used to measure cell surface APP levels. Results: We found that overexpression of SNX3 in HEK293T cells decreases the levels of secreted Aβ and soluble N-terminal APP fragments (sAPPβ). The reduction correlated with a decreased association of APP with BACE1, as revealed by BiFC. This effect may, in part, be explained by a reduced internalization of APP; SNX3 overexpression reduced APP internalization as determined by an α-bungarotoxin-binding assay, and caused increased APP levels on the cell surface, as shown by flow cytometry. In addition, SNX3 overexpression increased the cellular levels of full-length APP. Conclusion: These results provide evidence that SNX3 regulates Aβ production by influencing the internalization of APP.

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“…To circumvent this issue, in the past decade non-peptidomimetic molecules have been developed and proven more specific for BACE1 than peptidomimetic compounds [80]. Intriguingly, to our knowledge, very few studies take into consideration the dimerization of BACE1 when developing specific inhibitors, though evidence suggest that BACE1 dimers process APP more efficiently than BACE1 monomers [82,83]. Knowing the stoichiometry of APP cleavage by BACE1 might help generating more efficient BACE1 inhibitors.…”

Section: Bace1 Inhibitor Designmentioning

confidence: 99%