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. 2009 Jan 27;106(4):1261-6.
doi: 10.1073/pnas.0805453106. Epub 2009 Jan 21.

Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy

Cheryl A Hawkes  1 , Joanne McLaurin
Affiliations

Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy

Cheryl A Hawkes et al. Proc Natl Acad Sci U S A. .

Abstract

Cerebral amyloid angiopathy (CAA), the deposition of beta-amyloid (Abeta) peptides in leptomeningeal and cortical blood vessels, affects the majority of patients with Alzheimer's disease (AD). Evidence suggests that vascular amyloid deposits may result from impaired clearance of neuronal Abeta along perivascular spaces. We investigated the role of perivascular macrophages in regulating CAA severity in the TgCRND8 mouse model of AD. Depletion of perivascular macrophages significantly increased the number of thioflavin S-positive cortical blood vessels. ELISA confirmed that this increase was underscored by elevations in total vascular Abeta(42) levels. Conversely, stimulation of perivascular macrophage turnover reduced cerebral CAA load, an effect that was not mediated through clearance by microglia or astrocytes. These results highlight a function for the physiological role of perivascular macrophages in the regulation of CAA and suggest that selective targeting of perivascular macrophage activation might constitute a therapeutic strategy to clear vascular amyloid.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Administration of liposome-encapsulated clodronate depletes perivascular macrophages. (A and B) TgCRND8 mice injected with PBS liposomes (A) showed more CD163-positive perivascular macrophages (green) associated with GLUT-1- immunoreactive (red) blood vessels in the caudate putamen than those that received clodronate-containing liposomes (B). (C) Immunoblotting of right brain homogenates (30 μg/lane) demonstrated a significant reduction in CD206 levels (P = 0.002, n = 5) in mice receiving clodronate. (D and E) Photomicrographs showing that CD206 immunoreactivity is expressed by perivascular macrophages (red) but not by GFAP-immunoreactive astrocytes (D, green) or Iba1-positive microglia (E, green) in TgCRND8 mice. (Scale bars: A and B, 10 μm; D and E, 20 μm.)
Fig. 2.
Fig. 2.
Depletion of perivascular macrophages increases CAA severity. (A–C) Naive TgCRND8 mice (A) and those treated with PBS solution (B) show fewer thioS-positive cortical blood vessels than clodronate-treated mice (C). (D) Total cortical area covered in thioS-positive blood vessels was increased 5-fold in clodronate-treated animals (P = 0.01, n = 10). (E and F) No colocalization was found between thioS (green) and anti-perlecan (red) staining in PBS solution- (E) or clodronate-treated mice (F). (G and H) No differences in Aβ40-positive staining were noted between vehicle- (G) and clodronate-treated animals (H). (I and J) The number and intensity of Aβ42-positive cortical blood vessels was increased in mice treated with clodronate (J) versus control animals (I). (K–M) Total human Aβ42 levels in cortical blood vessels isolated from clodronate-treated mice (K) were significantly increased (P = 0.03, n = 12) compared with PBS solution-injected animals. Aβ42 levels were significantly decreased in the cortical samples (L; P = 0.04, n = 12) of clodronate-treated animals, but were not altered in plasma samples (M; P = 0.29). (N–P) Iba-1-positive microglia were noted throughout the cortex of vehicle- (N) and clodronate-treated mice (O). No differences were noted in Iba-1 levels (P) between treatment groups (P = 0.54, n = 4). Values represent mean ± SEM of samples analyzed in triplicate; *P < 0.05 and **P < 0.01. (Scale bars: A–C, 75 μm; E and F, 10 μm; G–J, 20 μm; N and M, 70 μm.)
Fig. 3.
Fig. 3.
Chitin administration stimulates perivascular macrophage turnover and clears CAA. (A and B) Most cells in PBS-treated mice showed colocalization of red and green dextran dyes (A, yellow-labeled cells), whereas chitin-treated animals (B) showed numerous singly, red-labeled macrophages (P = 0.01, n = 4). (C–E) The number of thioS-positive cortical blood vessels was significantly decreased following chitin treatment (D) compared with PBS solution-injected mice (C) (E, P = 0.01, n = 10). Histograms represent mean ± SEM values obtained from 3 brain sections per animal; **P < 0.01. (Scale bars: A and B, 10 μm; C and D, 75 μm.)
Fig. 4.
Fig. 4.
Perivascular macrophages clear CAA. (A–C) Chitin-treated mice showed no colocalization between thioS (A–C, green) and GFAP-positive astrocytes (A, red), nor with Iba1-positive microglia (B, red), which were however associated with parenchymal amyloid plaques (B, arrows). However, CD163-immunoreactive macrophages (C, red) colocalized with thioS-labeled vascular amyloid (C, green) in these mice. (D–G) No differences were noted between vehicle- (D) and chitin-treated animals (E) in brain tissue sections processed for anti-Aβ40 staining. A significant reduction in Aβ42-positive staining (F and G) was noted in chitin-treated animals (G) compared with controls (F). (H–J) Total human Aβ42 levels were significantly decreased in blood vessels (H, P = 0.04) and plasma samples (J, P = 0.04, n = 6) isolated from chitin-treated mice, but not in vessel-depleted cortical samples (I, P = 0.16). Values represent mean ± SEM of samples analyzed in triplicate; *P < 0.05. (Scale bars: A and B, 5 μm; C, 25 μm; D–G, 20 μm.)
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References

    1. Attems J, Lauda F, Jellinger KA. Unexpectedly low prevalence of intracerebral hemorrhages in sporadic cerebral amyloid angiopathy: an autopsy study. J Neurol. 2008;255:70–76. - PubMed
    1. Miao J, et al. Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol. 2005;167:505–515. - PMC - PubMed
    1. Shin HK, et al. Age-dependent cerebrovascular dysfunction in a transgenic mouse model of cerebral amyloid angiopathy. Brain. 2007;130:2310–2319. - PubMed
    1. Perlmutter LS. Microvascular pathology and vascular basement membrane components in Alzheimer's disease. Mol Neurobiol. 1994;9:33–40. - PubMed
    1. Tian J, et al. Relationships in Alzheimer's disease between the extent of Abeta deposition in cerebral blood vessel walls, as cerebral amyloid angiopathy, and the amount of cerebrovascular smooth muscle cells and collagen. Neuropathol Appl Neurobiol. 2006;32:332–340. - PubMed

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