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- W2896891630 abstract "Alzheimer's disease (AD) is a neurodegenerative process characterized, in part, by an accumulation of the beta-amyloid (Aβ) protein in the brain and cerebrovasculature. Mounting evidence suggests the excessive accumulation of Aβ in the AD brain is the result of impaired Aβ clearance mechanisms such as dysfunctional Aβ transport at the blood-brain barrier (BBB). The BBB transporter primarily responsible for the brain-to-blood elimination of Aβ is the low-density lipoprotein receptor (LDLR) and the LDLR-related protein 1 (LRP1). While LRP1 interacts with an array of ligands, one of the more closely associated is apolipoprotein E (apoE). Previously, we found an inverse relationship between LRP1 proteolysis (i.e. shedding) and Aβ transit across the BBB, one that is apoE isoform-specific. To elucidate the mechanisms driving these observations, we examined the interactions between apoE and a known LRP1 sheddase, matrix metallopeptidase 9 (MMP-9). We examined MMP-9 expression and activity according to apoE genotype in cerebrovascular tissue from human and mouse AD brains. In addition we looked at the effect of apoE genotype on MMP-9 dynamics in vitro. We found that MMP-9 expression and activity is increased in human cerebrovascular tissue in AD subjects and exhibits an apoE genotype difference. In both a cell-free assay and in primary human brain endothelial cells, MMP-9 activity was significantly attenuated by apoE in an isoform-specific manner (apoE2>apoE3>apoE4). In apoE4 animals, treatment with an MMP-9 inhibitor, SB-3CT, resulted in a significant reduction in brain LRP1 shedding and increased Aβ clearance from the brain to the periphery. Our findings indicate apoE4 is less effective in modulating MMP-9 activity and LRP1 shedding than the other apoE isoforms. These studies show that MMP-9 modulation can facilitate Aβ removal from the brain, which may provide a novel approach to the treatment of AD, particularly in individuals with an apoE4 genotype." @default.
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- W2896891630 date "2018-07-01" @default.
- W2896891630 modified "2023-10-16" @default.
- W2896891630 title "P1‐218: REGULATION OF MATRIX METALLOPEPTIDASE 9 BY APOLIPOPROTEIN E" @default.
- W2896891630 doi "https://doi.org/10.1016/j.jalz.2018.06.223" @default.
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