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Mol. Life Sci."],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Despite the neurodegenerative disorder Alzheimer\u2019s 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-\u03b2 (A\u03b2) due to impaired clearance mechanisms. A significant percentage is removed by low-density lipoprotein receptor-related protein 1 (LRP1)-mediated transport across the blood\u2013brain 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 A\u03b2 clearance remains elusive. By using an established BBB model, we identified reduced LRP1-mediated brain-to-blood A\u03b2 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 A\u03b2 burden across variants and aggregation state, which was not reproducible in brain endothelial-specific\n                    <jats:italic>LRP1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    5xFAD mice. The peripheral PCSK9 inhibition reduced A\u03b2 pathology in prefrontal cortex and hippocampus\u2013brain areas critically involved in memory processing\u2014and 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.\n                  <\/jats:p>","DOI":"10.1007\/s00018-022-04237-x","type":"journal-article","created":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T05:45:41Z","timestamp":1648446341000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["PCSK9 acts as a key regulator of A\u03b2 clearance across the blood\u2013brain barrier"],"prefix":"10.1007","volume":"79","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2899-6183","authenticated-orcid":false,"given":"Alexander D.","family":"Mazura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Ohler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6965-2264","authenticated-orcid":false,"given":"Steffen E.","family":"Storck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Kurtyka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franka","family":"Scharfenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Weggen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Becker-Pauly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1202-5489","authenticated-orcid":false,"given":"Claus U.","family":"Pietrzik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,27]]},"reference":[{"issue":"2","key":"4237_CR1","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.pharep.2014.09.004","volume":"67","author":"A Kumar","year":"2015","unstructured":"Kumar A, Singh A, Ekavali (2015) A review on Alzheimer\u2019s disease pathophysiology and its management: an update. 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