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The Effects of Cerebral Amyloid Angiopathy on Integrity of the Blood-Brain Barrier

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The Effects of Cerebral Amyloid Angiopathy on Integrity of the Blood-Brain Barrier

Shino Magaki et al. Neurobiol Aging.

Abstract

Cerebral amyloid angiopathy (CAA), in which amyloid accumulates predominantly in the walls of arterioles and capillaries, is seen in most patients with Alzheimer disease (AD) and may contribute to compromise of blood-brain barrier (BBB) function seen in AD. We investigated the effects of CAA on BBB integrity by examining the expression of the endothelial marker CD31, basement membrane protein collagen IV (COL4), tight junction protein claudin-5, and fibrinogen, a marker of BBB leakage, by immunohistochemistry in the occipital cortex of autopsy brains with AD and capillary CAA (CAA type 1; n = 8), AD with noncapillary CAA (CAA type 2; n = 10), and AD without CAA (n = 7) compared with elderly controls (n = 10). Given the difference in pathogenesis of capillary and noncapillary CAA, we hypothesize that features of BBB breakdown are observed only in capillary CAA. We found decreased expression of CD31 in AD subjects with CAA types 1 and 2 compared with AD without CAA and an increase in COL4 in AD without CAA compared with controls. Furthermore, there was increased immunoreactivity for fibrinogen in AD with CAA type 1 compared with controls. These findings suggest that capillary CAA is associated with morphologic and possibly physiologic alterations of the neurovascular unit and increased BBB permeability in AD.

Keywords: Alzheimer disease; Blood-brain barrier; Cerebral amyloid angiopathy; Immunohistochemistry.

Conflict of interest statement

Disclosure statement

The authors have no conflicts of interest to disclose.

Figures

Fig. 1.
Fig. 1.
Immunostaining for CD31 in the gray and white matter of AD subjects with CAA type 1, AD subjects with CAA type 2, AD subjects without CAA, and nondemented elderly subjects demonstrates (A) decreased staining for CD31 in the gray matter of AD subjects with CAA type 2 and (not shown) AD subjects with CAA type 1 compared with (B) AD subjects without CAA. This decrease is also seen in the white matter for AD patients with CAA type 2 compared with AD patients without CAA. (C) CD31 staining as mean ± SD. * p < 0.05, ** p < 0.01. Abbreviations: AD, Alzheimer disease; CAA, cerebral amyloid angiopathy; GM, gray matter; WM, white matter.
Fig. 2.
Fig. 2.
Immunohistochemistry for claudin-5 in the gray matter of (A) AD subjects with cerebral amyloid angiopathy (CAA) type 1, (not shown) AD subjects with CAA type 2, (not shown) AD subjects without CAA, and (B) nondemented elderly subjects demonstrates no significant difference in endothelial claudin-5 immunoreactivity between the groups. The white matter also shows no difference in claudin-5 staining. (C) Claudin-5 staining as mean ± SD. Abbreviations: AD, Alzheimer disease; CAA, cerebral amyloid angiopathy; GM, gray matter; WM, white matter.
Fig. 3.
Fig. 3.
Immunohistochemistry for collagen IV (COL4) in the gray and white matter of AD subjects with CAA type 1, AD subjects with CAA type 2, AD subjects without CAA, and nondemented elderly subjects shows increased COL4 staining in the gray matter in (A) AD subjects without CAA compared with (B) elderly controls. (C) COL4 staining as mean ± SD, * p < 0.05. Abbreviations: AD, Alzheimer disease; CAA, cerebral amyloid angiopathy; WM, white matter; GM, gray matter.
Fig. 4.
Fig. 4.
Immunostaining for fibrinogen in the gray and white matter of AD subjects with CAA type 1, AD subjects with CAA type 2, AD subjects without CAA, and nondemented elderly subjects demonstrates increased vascular and parenchymal fibrinogen immunoreactivity in the white matter of (A) AD patients with CAA type 1 compared with (B) elderly controls. (C) Fibrinogen staining as mean ± SD, *p < 0.05. Abbreviations: AD, Alzheimer disease; CAA, cerebral amyloid angiopathy; WM, white matter, GM, gray matter.

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