PCSK9 acts as a key regulator of Aβ clearance across the blood-brain barrier

被引:25
作者
Mazura, Alexander D. [1 ]
Ohler, Anke [1 ]
Storck, Steffen E. [1 ]
Kurtyka, Magdalena [1 ]
Scharfenberg, Franka [2 ]
Weggen, Sascha [3 ]
Becker-Pauly, Christoph [2 ]
Pietrzik, Claus U. [1 ]
机构
[1] Johannes Gutenberg Univ Mainz, Inst Pathobiochem, Univ Med Ctr, Duesbergweg 6, D-55128 Mainz, Germany
[2] Christian Albrecht Univ Kiel, Inst Biochem, D-24098 Kiel, Germany
[3] Heinrich Heine Univ Dusseldorf, Dept Neuropathol, D-40225 Dusseldorf, Germany
关键词
Alzheimer's disease; Amyloid-beta; Blood-brain barrier; Low-density lipoprotein receptor-related protein 1; Proprotein convertase subtilisin; kexin type 9; Monoclonal antibody therapy; RECEPTOR-RELATED PROTEIN-1; AMYLOID-BETA; ALZHEIMERS-DISEASE; LDL RECEPTOR; MOUSE-BRAIN; PEPTIDE; TRANSPORT; OLIGOMERS; MODEL; NEURODEGENERATION;
D O I
10.1007/s00018-022-04237-x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-beta (A beta) 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 A beta clearance remains elusive. By using an established BBB model, we identified reduced LRP1-mediated brain-to-blood A beta 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 beta burden across variants and aggregation state, which was not reproducible in brain endothelial-specific LRP1(-/-) 5xFAD mice. The peripheral PCSK9 inhibition reduced A beta 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.
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页数:15
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