Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-8302
Authors: | Mazura, Alexander D. Ohler, Anke Storck, Steffen E. Kurtyka, Magdalena Scharfenberg, Franka Weggen, Sascha Becker-Pauly, Christoph Pietrzik, Claus U. |
Title: | PCSK9 acts as a key regulator of Aβ clearance across the blood–brain barrier |
Online publication date: | 4-Jan-2023 |
Year of first publication: | 2022 |
Language: | english |
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: | 610 Medizin 610 Medical sciences |
Institution: | Johannes Gutenberg-Universität Mainz |
Department: | FB 04 Medizin |
Place: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-8302 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
License: | CC BY |
Information on rights of use: | https://creativecommons.org/licenses/by/4.0/ |
Journal: | Cellular and molecular life sciences 79 |
Pages or article number: | 212 |
Publisher: | Springer International Publishing AG |
Publisher place: | Cham (ZG) |
Issue date: | 2022 |
ISSN: | 1420-9071 |
Publisher DOI: | 10.1007/s00018-022-04237-x |
Appears in collections: | DFG-491381577-H |
Files in This Item:
File | Description | Size | Format | ||
---|---|---|---|---|---|
pcsk9_acts_as_a_key_regulator-20221114155950914.pdf | 1.69 MB | Adobe PDF | View/Open |