Korean J Radiol.  2018 Jun;19(3):498-507. 10.3348/kjr.2018.19.3.498.

Blood-Brain Barrier Disruption and Perivascular Beta-Amyloid Accumulation in the Brain of Aged Rats with Spontaneous Hypertension: Evaluation with Dynamic Contrast-Enhanced Magnetic Resonance Imaging

• Wang Y
• Zhang R
• Tao C
• Xu Z
• Chen W
• Wang C
• Song L
• Zheng J
• Gao F

• KMID: 2410821
• DOI: http://doi.org/10.3348/kjr.2018.19.3.498

Abstract

OBJECTIVE
Whether blood-brain barrier (BBB) disruption induced by chronic spontaneous hypertension is associated with beta-amyloid (Aβ) accumulation in the brain remains poorly understood. The purpose of this study was to investigate the relationship between BBB disruption and Aβ influx and accumulation in the brain of aged rats with chronic spontaneous hypertension.
MATERIALS AND METHODS
Five aged spontaneously hypertensive rats (SHRs) and five age-matched normotensive Wistar-Kyoto (WKY) rats were studied. The volume transfer constant (Ktrans) obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to evaluate BBB permeability in the hippocampus and cortex in vivo. The BBB tight junctions, immunoglobulin G (IgG), Aβ, and amyloid precursor protein (APP) in the hippocampus and cortex were examined with immunohistochemistry.
RESULTS
As compared with WKY rats, the Ktrans values in the hippocampus and cortex of the SHRs increased remarkably (0.316 ± 0.027 min−1 vs. 0.084 ± 0.017 min−1, p < 0.001 for hippocampus; 0.302 ± 0.072 min−1 vs. 0.052 ± 0.047 min−1, p < 0.001 for cortex). Dramatic occludin and zonula occludens-1 losses were detected in the hippocampus and cortex of SHRs, and obvious IgG exudation was found there. Dramatic Aβ accumulation was found and limited to the area surrounding the BBB, without extension to other parenchyma regions in the hippocampus and cortex of aged SHRs. Alternatively, differences in APP expression in the hippocampus and cortex were not significant.
CONCLUSION
Blood-brain barrier disruption is associated with Aβ influx and accumulation in the brain of aged rats with chronic spontaneous hypertension. DCE-MRI can be used as an effective method to investigated BBB damage.

Keyword

Alzheimer's disease; Transmembrane glycoprotein; Transfer constant; Tight junction protein

MeSH Terms

Alzheimer Disease
Amyloid
Animals
Blood-Brain Barrier*
Brain*
Hippocampus
Hypertension*
Immunoglobulin G
Immunohistochemistry
Magnetic Resonance Imaging*
Methods
Occludin
Permeability
Rats*
Rats, Inbred SHR
Rats, Inbred WKY
Tight Junctions
Amyloid
Immunoglobulin G
Occludin

Figure

• 

  Fig. 1 ROI definition in right hippocampus and cortex of rats. Hippocampus was defined at bregma −3.60 mm (ROI 1) and bregma −5.60 mm (ROI 3) on coronal T2WI. Cortex was defined at bregma -3.60 mm (ROI 2) and bregma −5.60 mm (ROI 4) on coronal T2WI. R = right, ROI = region of interest, T2WI = T2-weighted imaging

• 

  Fig. 2 BBB permeability increase in hippocampus and cortex of aged SHRs. A. Hippocampus and cortex of aged SHRs and age-matched WKY rats at bregma −3.60 mm (slice 1). B. Hippocampus and cortex of aged SHRs and age-matched WKY rats at bregma −5.60 mm (slice 2). Left column shows hippocampus and cortex on T2WI. Middle column shows Ktrans maps of hippocampus. Right column shows Ktrans maps of cortex. Color-coded Ktrans values range between 0.0 min−1 and 3.0 min−1, with dark blue indicating 0.0 min−1, green indicating 1.5 min−1, and red indicating 3.0 min−1. C. Ktrans values of right hippocampus of aged SHRs and age-matched WKY rats. D. Ktrans values of right cortex of aged SHRs and age-matched WKY rats. Values are expressed as mean ± standard deviation. BBB = blood-brain barrier, Ktrans = volume transfer constant, SHRs = spontaneously hypertensive rats, WKY = Wistar-Kyoto

• 

  Fig. 3 Occludin and ZO-1 decrease in hippocampus of aged SHRs. A. Occludin (red) and GFAP (green) immunoreactivity in hippocampus of age-matched WKY rats (upper row) and aged SHRs (lower row). B. ZO-1 (red) and GFAP (green) immunoreactivity in hippocampus of age-matched WKY rats (upper row) and aged SHRs (lower row). White asterisks indicate BBB surrounded by astrocyte processes. White arrows refer to decrease of occludin or ZO-1. Bar = 50 μm. GFAP = glial fibrillary acidic protein, ZO-1 = zonula occludens-1

• 

  Fig. 4 Occludin and ZO-1 decrease in cortex of aged SHRs. A.Occludin (red) and GFAP (green) immunoreactivity in cortex of age-matched WKY rats (upper row) and aged SHRs (lower row). B. ZO-1 (red) and GFAP (green) immunoreactivity in cortex of age-matched WKY rats (upper row) and aged SHRs (lower row). White asterisks indicate BBB surrounded by astrocyte processes. White arrows refer to decrease of occludin or ZO-1. Bar = 50 μm.

• 

  Fig. 5 IgG leakage and Aβ accumulation in hippocampus and cortex of aged SHRs. A. IgG (green) and GFAP (red) immunoreactivity in hippocampus (upper row) and cortex (lower row) of aged SHRs and age-matched WKY rats. Black asterisks indicate cerebrovascular lumen surrounded by astrocyte processes. White arrows refer to IgG leakage and accumulation surrounding BBB. B. Aβ (red) and GFAP (green) immunoreactivity in hippocampus (upper row) and cortex (lower row) of aged SHRs and agematched WKY rats. White asterisks indicate cerebrovascular lumen surrounded by astrocyte processes. White arrows refer to Aβ accumulation surrounding BBB. Bar = 50 μm. C. FAU values of IgG in hippocampus and cortex of aged SHRs and age-matched WKY rats. D. FAU values of Aβ in hippocampus and cortex of aged SHRs and age-matched WKY rats. Values are expressed as mean ± standard deviation. Aβ = beta-amyloid, DAPI = 4', 6-diamidino-2-phenylindole, FAU = fluorescence arbitrary unit, IgG = immunoglobulin G

• 

  Fig. 6 APP expression in hippocampus and cortex of aged SHRs and age-matched WKY rats. A. APP immunoreactivity in hippocampus (upper row) and cortex (lower row) of aged SHRs and age-matched WKY rats. Bar = 50 μm. B. FAU values of APP in hippocampus and cortex of aged SHRs and age-matched WKY rats. Values are expressed as mean ± standard deviation. APP = amyloid precursor protein

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