Autoren:	Mazura, Alexander D. Ohler, Anke Storck, Steffen E. Kurtyka, Magdalena Scharfenberg, Franka Weggen, Sascha Becker-Pauly, Christoph Pietrzik, Claus U.
Titel:	PCSK9 acts as a key regulator of Aβ clearance across the blood–brain barrier
Online-Publikationsdatum:	4-Jan-2023
Erscheinungsdatum:	2022
Sprache des Dokuments:	Englisch
Zusammenfassung/Abstract:	Despite the neurodegenerative disorder Alzheimer’s disease (AD) is the most common form of dementia in late adult life, there is currently no therapy available to prevent the onset or slow down the progression of AD. The progressive cognitive decline in AD correlates with a successive accumulation of cerebral amyloid-β (Aβ) due to impaired clearance mechanisms. A significant percentage is removed by low-density lipoprotein receptor-related protein 1 (LRP1)-mediated transport across the blood–brain barrier (BBB) into the periphery. Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to members of the low-density lipoprotein receptor protein family at the cell surface and targets them for lysosomal degradation, which reduces the number of functional receptors. However, the adverse impact of PCSK9 on LRP1-mediated brain Aβ clearance remains elusive. By using an established BBB model, we identified reduced LRP1-mediated brain-to-blood Aβ clearance due to PCSK9 across different endothelial monolayer in vitro. Consequently, the repetitive application of FDA-approved monoclonal anti-PCSK9 antibodies into 5xFAD mice decreased the cerebral Aβ burden across variants and aggregation state, which was not reproducible in brain endothelial-specific LRP1−/− 5xFAD mice. The peripheral PCSK9 inhibition reduced Aβ pathology in prefrontal cortex and hippocampus–brain areas critically involved in memory processing—and prevented disease-related impairment in hippocampus-dependent memory formation. Our data suggest that peripheral inhibition of PCSK9 by already available therapeutic antibodies may be a novel and easily applicable potential AD treatment.
DDC-Sachgruppe:	610 Medizin 610 Medical sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 04 Medizin
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-8302
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/4.0/
Zeitschrift:	Cellular and molecular life sciences 79
Seitenzahl oder Artikelnummer:	212
Verlag:	Springer International Publishing AG
Verlagsort:	Cham (ZG)
Erscheinungsdatum:	2022
ISSN:	1420-9071
DOI der Originalveröffentlichung:	10.1007/s00018-022-04237-x
Enthalten in den Sammlungen:	DFG-491381577-H