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, 23 (3), 303-10

Deficiency in Mural Vascular Cells Coincides With Blood-Brain Barrier Disruption in Alzheimer's Disease

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Deficiency in Mural Vascular Cells Coincides With Blood-Brain Barrier Disruption in Alzheimer's Disease

Jesse D Sengillo et al. Brain Pathol.

Abstract

Neurovascular dysfunction contributes to Alzheimer's disease (AD). Cerebrovascular abnormalities and blood-brain barrier (BBB) damage have been shown in AD. The BBB dysfunction can lead to leakage of potentially neurotoxic plasma components in brain that may contribute to neuronal injury. Pericytes are integral in maintaining the BBB integrity. Pericyte-deficient mice develop a chronic BBB damage preceding neuronal injury. Moreover, loss of pericytes was associated with BBB breakdown in patients with amyotrophic lateral sclerosis. Here, we demonstrate a decrease in mural vascular cells in AD, and show that pericyte number and coverage in the cortex and hippocampus of AD subjects compared with neurologically intact controls are reduced by 59% and 60% (P < 0.01), and 32% and 33% (P < 0.01), respectively. An increase in extravascular immunoglobulin G (IgG) and fibrin deposition correlated with reductions in pericyte coverage in AD cases compared with controls; the Pearson's correlation coefficient r for the magnitude of BBB breakdown to IgG and fibrin vs. reduction in pericyte coverage was -0.96 (P < 0.01) and -0.81 (P < 0.01) in the cortex, respectively, and -0.86 (P < 0.01) and -0.98 (P < 0.01) in the hippocampus, respectively. Thus, deficiency in mural vascular cells may contribute to disrupted vascular barrier properties and resultant neuronal dysfunction during AD pathogenesis.

Conflict of interest statement

Conflict of interest The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Spatial representation of pericytes within the neurovascular unit in the human cortex
Low-magnification confocal microscopy analysis illustrating structural relationships between GFAP-positive astrocytes (green), PDGFRβ-positive pericytes on brain capillaries (red) and lectin-positive endothelial cells (blue) in human frontal cortex. Inset - high-magnification view of cerebrovascular capillary in cross-section: GFAP-positive astrocyte end foot processes (green), PDGFRβ-positive pericyte processes (red) and lectin-positive brain capillary endothelial cells (blue); purple (merged), shows colocalization of pericytes and brain capillary endothelial cells.
Figure 2
Figure 2. Pericyte number and coverage of cerebral capillaries are reduced in Alzheimer’s disease
(A) Representative confocal microscopy analysis of PDGFRβ immunodetection (red, left) and colocalization of PDGFRβ-positive mural cells (red, right) and lectin-positive brain endothelial cells (green, right) illustrating mural cell coverage of brain capillaries (yellow-merged, right) in the frontal cortex of an age-matched neurologically intact control and AD patient. (B) Quantification of PDGFRβ-positive pericytes per mm2 of lectin-positive brain capillaries in the frontal cortex and CA1 hippocampal subfield in neurologically intact controls and AD cases. Mean ± s.e.m., n = 6 individuals per group for each brain region. (C) Quantification of PDGFRβ-positive pericyte coverage of lectin-positive brain capillaries in the frontal cortex and CA1 hippocampal subfield in neurologically intact controls and AD cases. Mean ± s.e.m., n = 6 individuals per group for each brain region. (D) Representative confocal microscopy analysis of mural cell-specfic N-Aminopeptidase (CD13) immunodetection (red, left) and colocalization of CD13-positive mural cells (red, right) and lectin-positive brain endothelium (green, right) illustrating mural cell coverage of brain microvessels (yellow-merged, right) in the CA1 hippocampal subfield of an age-matched neurologically intact control and AD patient. (E) Quantification of CD13-positive pericyte coverage of lectin-positive brain capillaries in the frontal cortex and CA1 hippocampal subfield in age-matched neurologically intact controls and AD cases. Mean ± s.e.m., n = 6 individuals per group for each brain region.
Figure 3
Figure 3. Blood-brain barrier IgG leakage correlates with pericyte reduction in AD
(A) Representative confocal microscopy analysis of extravascular IgG accumulation (red) and lectin-positive brain microvessels (green) in the CA1 hippocampal subfield in an age-matched neurologically intact control and AD patient. (B) Quantification of extravascular IgG deposits in the frontal cortex and CA1 hippocampal subfield in age-matched neurologically intact controls and AD cases. Mean ± s.e.m., n = 6 individuals per group for each brain region. (C, D) Negative correlation between extravascular IgG accumulation and loss of pericyte coverage of brain capillaries in the frontal cortex (C) and CA1 hippocampal subfield (D) in AD cases compared to neurologically intact controls; n = 6 individuals per group for each brain region.
Figure 4
Figure 4. Blood-brain barrier fibrin leakage correlates with pericyte reduction in AD
(A) Representative confocal microscopy analysis of extravascular fibrin accumulation (red) and lectin-positive brain microvessels (green) in the CA1 hippocampal subfield in an age-matched neurologically intact control and AD patient. (B) Quantification of extravascular fibrin deposits in the frontal cortex and CA1 hippocampal subfield in neurologically intact controls and AD cases. Mean ± s.e.m., n = 6 individuals per group for each brain region. (C, D) Negative correlation between extravascular fibrin accumulation and loss of pericyte coverage of brain capillaries in the frontal cortex (D) and CA1 hippocampal subfield (E) in AD cases compared to neurologically intact controls; n = 6 individuals per group for each brain region.
Figure 5
Figure 5. Hippocampal Aβ deposition correlates with pericyte reduction in AD
(A) Representative confocal microscopy analysis of Aβ-positive deposits (red) and lectin-positive brain capillaries (green) in the CA1 hippocampal subfield in a neurologically intact control and AD patient. (B) Quantification of Aβ deposits in the CA1 hippocampal subfield in neurologically intact controls and AD cases. Mean ± s.e.m., n = 6 individuals per group. (C) Negative correlation between Aβ deposits and loss of pericyte coverage of brain capillaries in the hippocampus. (D) Representative confocal microscopy analysis showing extravascular IgG accumulation (red), Aβ-positive deposition (green) and a lectin-positive brain capillary in the hippocampus (white); yellow (merged), shows colocalization of IgG and Aβ deposits.

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