The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM

Steffen E. Storck; Anika M.S. Hartz; Jessica Bernard; Andrea Wolf; André Kachlmeier; Anne Mahringer; Sascha Weggen; Jens Pahnke; Claus U. Pietrzik

doi:10.1016/j.bbi.2018.07.017

The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM

Steffen E. Storck, Anika M.S. Hartz, Jessica Bernard, Andrea Wolf, André Kachlmeier, Anne Mahringer, Sascha Weggen, Jens Pahnke, Claus U. Pietrzik

Research output: Contribution to journal › Article › peer-review

114 Scopus citations

Abstract

The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic hallmark of Alzheimer's disease (AD). The blood-brain barrier (BBB) provides a large surface area and has been shown to be an important mediator for removal of brain Aβ. Both, the ABC transporter P-glycoprotein (ABCB1/P-gp) and the receptor low-density lipoprotein receptor-related protein 1 (LRP1) have been implicated to play crucial roles in Aβ efflux from brain. Here, with immunoprecipitation experiments, co-immunostainings and dual inhibition of ABCB1/P-gp and LRP1, we show that both proteins are functionally linked, mediating a concerted transcytosis of Aβ through endothelial cells. Late-onset AD risk factor Phosphatidylinositol binding clathrin assembly protein (PICALM) is associated with both ABCB1/P-gp and LRP1 representing a functional link and guiding both proteins through the brain endothelium. Together, our results give more mechanistic insight on Aβ transport across the BBB and show that the functional interplay of different clearance proteins is needed for the rapid removal of Aβ from the brain.

Original language	English
Pages (from-to)	21-33
Number of pages	13
Journal	Brain, Behavior, and Immunity
Volume	73
DOIs	https://doi.org/10.1016/j.bbi.2018.07.017
State	Published - Oct 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Inc.

Funding

PROP-AD is an EU Joint Programme – Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND – www.jpnd.eu (AKA #301228 – Finland, BMBF #01ED1605 – Germany, CSO-MOH #30000-12631 – Israel, NFR #260786 – Norway, SRC #2015-06795 – Sweden). The project was funded by collaborative grants to Jens Pahnke and Claus Pietrzik of the Deutsche Forschungsgemeinschaft (PA930/12, PI 379/8-1) and JPND joint EU grant (PROP-AD: BMBF #01ED1605 – Germany, NFR #260786 – Norway) within Horizon 2020/European Union (#643417 – JPco-fuND agreement) and the intramural funding program of the University Medical Center of the Johannes-Gutenberg University Mainz to Steffen Storck. This project was also supported by grant number 2R01AG039621 from the National Institute on Aging (to A.M.S.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. NeuroGeM is an EU Joint Programme – Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND – www.jpnd.eu (CIHR – Canada, BMBF – Germany, NRF #247179 – Norway, ZonMW – The Netherlands). The work of J.P. was also financed by the following grants: Deutsche Forschungsgemeinschaft/Germany (DFG PA930/9); Leibniz Society/Germany (SAW-2015-IPB-2); HelseSØ/Norway (2016062); VIAA/Latvia (NFI/R/2014/023); Norsk forskningsrådet/Norway (247179 NeuroGeM, 251290 FRIMEDIO).

Funders	Funder number
Deutsche Forschungsgemeinschaft/Germany	DFG PA930/9
HelseSØ	2016062, NFI/R/2014/023
Leibniz Society/Germany	SAW-2015-IPB-2
Norsk forskningsrådet/Norway	247179 NeuroGeM, 251290
National Institute on Aging	RF1AG039621
National Institute on Aging
EU Joint Programme – Neurodegenerative Disease Research	301228
EU Joint Programme – Neurodegenerative Disease Research
Canadian Institutes of Health Research
European Commission
Deutsche Forschungsgemeinschaft	PI 379/8-1, PA930/12
Deutsche Forschungsgemeinschaft
ZonMw Memorabel
Bundesministerium für Bildung und Forschung	01ED1605, 260786, 30000-12631, 2015-06795, 643417
Bundesministerium für Bildung und Forschung
National Research Foundation of Korea	247179
National Research Foundation of Korea
Johannes Gutenberg-Universität Mainz

Keywords

ABC transporter B1/P-glycoprotein (ABCB1/P-gp)
Alzheimer's disease (AD)
Amyloid-beta (Aβ)
Blood-brain barrier (BBB)
Clearance
Endothelial cell
Endothelium
Low-density lipoprotein receptor-related protein 1 (LRP1)
Phosphatidylinositol-binding clathrin assembly protein (PICALM)
Transcytosis

ASJC Scopus subject areas

Immunology
Endocrine and Autonomic Systems
Behavioral Neuroscience

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10.1016/j.bbi.2018.07.017

Cite this

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title = "The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM",

abstract = "The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic hallmark of Alzheimer's disease (AD). The blood-brain barrier (BBB) provides a large surface area and has been shown to be an important mediator for removal of brain Aβ. Both, the ABC transporter P-glycoprotein (ABCB1/P-gp) and the receptor low-density lipoprotein receptor-related protein 1 (LRP1) have been implicated to play crucial roles in Aβ efflux from brain. Here, with immunoprecipitation experiments, co-immunostainings and dual inhibition of ABCB1/P-gp and LRP1, we show that both proteins are functionally linked, mediating a concerted transcytosis of Aβ through endothelial cells. Late-onset AD risk factor Phosphatidylinositol binding clathrin assembly protein (PICALM) is associated with both ABCB1/P-gp and LRP1 representing a functional link and guiding both proteins through the brain endothelium. Together, our results give more mechanistic insight on Aβ transport across the BBB and show that the functional interplay of different clearance proteins is needed for the rapid removal of Aβ from the brain.",

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doi = "10.1016/j.bbi.2018.07.017",

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AU - Storck, Steffen E.

AU - Hartz, Anika M.S.

AU - Bernard, Jessica

AU - Wolf, Andrea

AU - Kachlmeier, André

AU - Mahringer, Anne

AU - Weggen, Sascha

AU - Pahnke, Jens

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AB - The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic hallmark of Alzheimer's disease (AD). The blood-brain barrier (BBB) provides a large surface area and has been shown to be an important mediator for removal of brain Aβ. Both, the ABC transporter P-glycoprotein (ABCB1/P-gp) and the receptor low-density lipoprotein receptor-related protein 1 (LRP1) have been implicated to play crucial roles in Aβ efflux from brain. Here, with immunoprecipitation experiments, co-immunostainings and dual inhibition of ABCB1/P-gp and LRP1, we show that both proteins are functionally linked, mediating a concerted transcytosis of Aβ through endothelial cells. Late-onset AD risk factor Phosphatidylinositol binding clathrin assembly protein (PICALM) is associated with both ABCB1/P-gp and LRP1 representing a functional link and guiding both proteins through the brain endothelium. Together, our results give more mechanistic insight on Aβ transport across the BBB and show that the functional interplay of different clearance proteins is needed for the rapid removal of Aβ from the brain.

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The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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