Apolipoprotein E Isoforms Differentially Regulate Matrix Metallopeptidase 9 Function in Alzheimer’s Disease

Ringland, Charis (2020). Apolipoprotein E Isoforms Differentially Regulate Matrix Metallopeptidase 9 Function in Alzheimer’s Disease. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00011bec

Abstract

Apolipoprotein E (APOE) is a major genetic risk factor for Alzheimer’s disease (AD) and has been shown to influence amyloid-β (Aβ) clearance from the brain in an isoform-specific manner. Our prior work showed Aβ transit across the blood-brain-barrier was reduced by apoE4, compared to other apoE isoforms, due to elevated lipoprotein receptor shedding in brain endothelia. Recently, we demonstrated matrix metallopeptidase 9 (MMP-9) induces lipoprotein receptor proteolysis in an apoE isoform-dependent manner, which impacts Aβ elimination from the brain. The current studies interrogated the relationship between apoE and MMP-9 and found apoE dose-dependently reduced MMP-9 activity in a cell-free assay, with apoE4 showing a significantly weaker ability to inhibit MMP-9 function than apoE2 or apoE3. Moreover, these effects may be due to the reduced binding affinity of apoE4 for MMP-9 compared to apoE2 and apoE3 as revealed by kinetic binding studies. Elevated MMP-9 expression and activity was observed in the cerebrovasculature of both human and animal AD brain specimens with an APOE4 genotype. The apoE isoforms also lead to altered levels of MMP-9 secreted from brain endothelia cultures (apoE2<apoE3=apoE4). Both the expression and secretion of MMP-9 were more pronounced upon insult, suggesting a combined influence of AD and APOE genotype. Collectively, these findings suggest a role for apoE in regulating MMP-9 disposition in the brain, which could have profound consequences for a variety of neurodegenerative diseases. With respect to AD, genetic deletion of the MMP-9 gene in 5xFAD mice rescued deficits in sociability, social recognition memory and anxiety disinhibition, signifying an important role for MMP-9 in the behavioral dysfunction inherent in AD. These observations did not appear to be due to changes in brain Aβ levels or lipoprotein receptor shedding, suggesting the behavioral improvements resulting from MMP-9 gene removal were mediated through alternative mechanisms. In total, modulating MMP-9 may represent a promising therapeutic strategy for the treatment of AD and other neurological disorders.

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