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, 36 (1), 216-27

Accelerated Pericyte Degeneration and Blood-Brain Barrier Breakdown in Apolipoprotein E4 Carriers With Alzheimer's Disease

Accelerated Pericyte Degeneration and Blood-Brain Barrier Breakdown in Apolipoprotein E4 Carriers With Alzheimer's Disease

Matthew R Halliday et al. J Cereb Blood Flow Metab.

Abstract

The blood–brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer’s disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 (APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD (APOE4 >APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA–MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.

Figures

Figure 1.
Figure 1.
Accelerated pericyte degeneration and microvascular reductions in APOE4 carriers with Alzheimer’s disease. (A) Representative confocal microscopic analysis of PDGFRβ-positive mural cells (red) and lectin-positive endothelial profiles (green) demonstrating mural cell coverage of brain capillaries (yellow-merged) in the frontal cortex of an age-matched neurologically intact control (top), an AD APOE3/APOE3 patient (middle), and an AD APOE4/APOE3 patient (bottom). Scale bars, 25 µm. (B) Quantification of PDGFRβ-positive cell bodies in the frontal cortex of neurologically intact controls, AD APOE3 group, and AD APOE4 group expressed per mm2 of tissue section. See Supplementary Figure 1 for representative images of PDGFRβ+/DAPI+ pericyte cell bodies. (C) Quantification of PDGFRβ-positive pericyte coverage of lectin-positive vascular endothelial profiles in the frontal cortex of neurologically intact controls, AD APOE3 group, and AD APOE4 group. (D) Quantification of total length of lectin-positive brain endothelial profiles in the frontal cortex of neurologically intact controls, AD APOE3 group, and AD APOE4 group. (E) Positive correlation between total length of lectin-positive endothelial vascular profiles and PDGFRβ-positive pericyte coverage of brain capillaries in the frontal cortex of neurologically intact controls (blue), AD APOE3 patients (red), and AD APOE4 patients (green; n = 27). Single data points are from all studied controls and AD patients (n = 27). Mean±s.e.m., n = 9 for non-AD control; n = 6 for AD APOE3 group; and n = 12 for AD APOE4 group. r = Pearson’s coefficient. AD, Alzheimer’s disease; APOE, apolipoprotein E; DAPI, 4′,6-diamidino-2-phenylindole.
Figure 2.
Figure 2.
Increased fibrin and immunoglobulin G (IgG) extravascular deposits in APOE4 carriers with Alzheimer’s disease correlates with pericyte degeneration. (A) Representative confocal microscopic analysis of fibrin extravascular deposits (red) and lectin-positive endothelial profiles (green) in the frontal cortex of an age-matched neurologically intact control (left), an AD APOE3/APOE3 patient (middle), and an AD APOE4/APOE3 patient (right). Scale bar, 25 µm. (B) Quantification of fibrin extravascular fibrin in the frontal cortex in neurologically intact controls, AD APOE3 group, and AD APOE4 group. (C) Negative correlation between fibrin extravascular deposits and PDGFRβ-positive pericyte coverage of brain capillaries in the frontal cortex of neurologically intact controls (blue), AD APOE3 patients (red), and AD APOE4 patients (green). Single data points are from all controls and AD patients (n = 27). (D) Representative confocal microscopic analysis of IgG extravascular deposits (red) and lectin-positive endothelial profiles (green) in the frontal cortex of an age-matched neurologically intact control (left), an AD APOE3/APOE3 patient (middle), and an AD APOE4/APOE3 patient (right). Scale bar, 25 µm. (E) Quantification of IgG extravascular deposits in the frontal cortex in neurologically intact controls, AD APOE3 group, and AD APOE4 group. (F) Negative correlation between IgG extravascular deposits and PDGFRβ-positive pericyte coverage of brain capillaries in the frontal cortex of neurologically intact controls (blue), AD APOE3 patients (red), and AD APOE4 patients (green). Single data points are from all controls and AD patients (n = 27). Mean±s.e.m., n = 9 for non-AD control; n = 6 for AD APOE3 group; and n = 12 for AD APOE4 group. r = Pearson’s coefficient. AD, Alzheimer’s disease; APOE, apolipoprotein E.
Figure 3.
Figure 3.
Lipoprotein receptor-related protein 1 (LRP1) levels are reduced in pericytes and brain endothelial cells in Alzheimer’s disease irrespective of APOE genotype. (A) Representative confocal microscopic analysis of LRP-1 immunodetection (red), and colocalization of LRP-1 (red) with PDGFRβ-positive pericytes (green, yellow-merged) and lectin-positive endothelial profiles (blue, magenta-merged) in the frontal cortex of an age-matched neurologically intact control (top) and an AD APOE4/APOE3 patient (bottom). Scale bar, 20 µm. (B) Quantification of LRP-1-positive signal colocalizing with PDGFRβ-positive pericytes in the frontal cortex of neurologically intact controls, AD APOE3 group and AD APOE4 group. (C) Quantification of LRP-1-positive signal colocalizing with lectin-positive brain endothelial cells in the frontal cortex of neurologically intact controls, AD APOE3 group, and AD APOE4 group. Mean±s.e.m., n = 9 for non-AD control; n = 6 for AD APOE3 group; and n = 12 for AD APOE4 group. AD, Alzheimer’s disease; APOE, apolipoprotein E.
Figure 4.
Figure 4.
Cyclophilin A levels are elevated in pericytes and brain endothelial cells in APOE4 carriers with Alzheimer’s disease. (A) Representative confocal microscopic analysis of cyclophilin A (CypA) immunodetection (red) and colocalization of CypA (red) with PDGFRβ-positive pericytes (green, yellow-merged) and lectin-positive endothelial profiles (blue, magenta-merged) in the frontal cortex of an age-matched neurologically intact control (top), an AD APOE3/APOE3 patient (middle), and an AD APOE4/APOE3 patient (below). Scale bar, 15 µm. (B) Quantification of CypA-positive signal colocalizing with PDGFRβ-positive pericytes in the frontal cortex of neurologically intact controls, AD APOE3 group, and AD APOE4 group. (C) Quantification of CypA-positive signal colocalizing with lectin-positive brain endothelial cells in the frontal cortex of neurologically intact controls, AD APOE3 group, and AD APOE4 group. Mean ± s.e.m., n = 9 for non-AD control; n = 6 for AD APOE3 group; and n = 12 for AD APOE4 group. AD, Alzheimer’s disease; APOE, apolipoprotein E.
Figure 5.
Figure 5.
Matrix metalloproteinase-9 levels are elevated in pericytes and brain endothelial cells in APOE4 carriers with Alzheimer’s disease. (A) Representative confocal microscopic analysis of matrix metalloproteinase-9 (MMP-9) immunodetection (red) and colocalization of MMP-9 (red) with PDGFRβ-positive pericytes (green, yellow-merged) and lectin-positive brain endothelial cells (blue, magenta-merged) in the frontal cortex of an age-matched neurologically intact control (top), an AD APOE3/APOE3 patient (middle), and an AD APOE4/APOE3 patient (below). Scale bar, 15 µm. (B) Quantification of MMP-9-positive signal colocalizing with PDGFRβ-positive pericytes in the frontal cortex of neurologically intact controls, AD APOE3 group, and AD APOE4 group. (C) Quantification of MMP-9-positive signal colocalizing with lectin-positive brain endothelial cells in the frontal cortex of neurologically intact controls, AD APOE3 group and AD APOE4 group. Mean ± s.e.m., n = 9 for non-AD control; n = 6 for AD APOE3 group; and n = 12 for AD APOE4 group.

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