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Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1) overexpression reduces APP processing and increases alpha- versus beta-secretase activity, in vitro

Jepsen, Wayne M., De Both, Matthew, Siniard, Ashley L., Ramsey, Keri, Piras, Ignazio S., Naymik, Marcus, Henderson, Adrienne, Huentelman, Matthew J.·2020
DOI 10.1101/2020.05.20.105064
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Abstract

The organic anion transporter Adenosine triphosphate Binding Cassette subfamily C member 1 ( ABCC1 ), also known as MRP1 , has been demonstrated in murine models of Alzheimer’s disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood-brain barrier to the periphery, and that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that it’s overexpression significantly reduces Abeta production and increases the ratio of alpha- versus beta-secretase mediated cleavage of the Amyloid Precursor Protein (APP), likely via indirect modulation of alpha-, beta-, and gamma-secretase activity.

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  • In addition to APP, there was an increase in the surface expression of several proteins involved in APP processing and amyloid-β response in VPS35-suppressed neuronal cultures, including BACE1, APLP1, APLP2, ABCC1, EPHA4, IGFR1, and SYP.

    “In addition to APP, we found an increase in the surface expression of several proteins involved in APP processing and amyloid-β response in the VPS35 suppressed neuronal cultures.These included βsecretase 1 (BACE1), [92], APP-like β-secretase substrates APLP1 and APLP2 [93], transporter ABCC1 [94][95][96], ephrin type-A receptor 4 (EPHA4) [97,98], and insulin-like growth factor-1 (IGFR1) [99], and”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [94]

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Metadata

Authors
Jepsen, W. M., De Both, M., Siniard, A. L., Ramsey, K., Piras, I. S., Naymik, M., Henderson, A., & Huentelman, M. J.
Publisher
openRxiv
Published
2020-05-21
DOI
10.1101/2020.05.20.105064
Cited by
1
References
1
Type
Preprint
Licence
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)

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