Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-?42 by LRP1-dependent apolipoprotein E isoform-specific mechanism.

ABSTRACT:

Background

Clearance at the blood-brain barrier (BBB) plays an important role in removal of Alzheimer's amyloid-? (A?) toxin from brain both in humans and animal models. Apolipoprotein E (apoE), the major genetic risk factor for AD, disrupts A? clearance at the BBB. The cellular and molecular mechanisms, however, still remain unclear, particularly whether the BBB-associated brain capillary pericytes can contribute to removal of aggregated A? from brain capillaries, and whether removal of A? aggregates by pericytes requires apoE, and if so, is A? clearance on pericytes apoE isoform-specific.

Methods

We performed immunostaining for A? and pericyte biomarkers on brain capillaries (Swe/0 mice and littermate controls. Human Cy3-A?42 uptake by pericytes was studied on freshly isolated brain slices from control mice, pericyte LRP1-deficient mice (Lrp^lox/lox;Cspg4-Cre) and littermate controls. Clearance of aggregated A?42 by mouse pericytes was studied on multi-spot glass slides under different experimental conditions including pharmacologic and/or genetic inhibition of the low density lipoprotein receptor related protein 1 (LRP1), an apoE receptor, and/or silencing mouse endogenous Apoe in the presence and absence of human astrocyte-derived lipidated apoE3 or apoE4. Student's t-test and one-way ANOVA followed by Bonferroni's post-hoc test were used for statistical analysis.

Results

First, we found that 35% and 60% of brain capillary pericytes accumulate A? in AD patients and 8.5-month-old APP^Sw/0 mice, respectively, compared to negligible uptake in controls. Cy3-A?42 species were abundantly taken up by pericytes on cultured mouse brain slices via LRP1, as shown by both pharmacologic and genetic inhibition of LRP1 in pericytes. Mouse pericytes vigorously cleared aggregated Cy3-A?42 from multi-spot glass slides via LRP1, which was inhibited by pharmacologic and/or genetic knockdown of mouse endogenous apoE. Human astrocyte-derived lipidated apoE3, but not apoE4, normalized A?42 clearance by mouse pericytes with silenced mouse apoE.

Conclusions

Our data suggest that BBB-associated pericytes clear A? aggregates via an LRP1/apoE isoform-specific mechanism. These data support the role of LRP1/apoE interactions on pericytes as a potential therapeutic target for controlling A? clearance in AD.

SUBMITTER: Ma Q 

PROVIDER: S-EPMC6194676 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature