Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease - PubMed (original) (raw)

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Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease

Roy O Weller et al. Brain Pathol. 2008 Apr.

Abstract

Alzheimer's disease is the commonest dementia. One major characteristic of its pathology is accumulation of amyloid-beta (Abeta) as insoluble deposits in brain parenchyma and in blood vessel walls [cerebral amyloid angiopathy (CAA)]. The distribution of Abeta deposits in the basement membranes of cerebral capillaries and arteries corresponds to the perivascular drainage pathways by which interstitial fluid (ISF) and solutes are eliminated from the brain--effectively the lymphatic drainage of the brain. Theoretical models suggest that vessel pulsations supply the motive force for perivascular drainage of ISF and solutes. As arteries stiffen with age, the amplitude of pulsations is reduced and insoluble Abeta is deposited in ISF drainage pathways as CAA, thus, further impeding the drainage of soluble Abeta. Failure of perivascular drainage of Abeta and deposition of Abeta in the walls of arteries has two major consequences: (i) intracerebral hemorrhage associated with rupture of Abeta-laden arteries in CAA; and (ii) Alzheimer's disease in which failure of elimination of ISF, Abeta and other soluble metabolites from the brain alters homeostasis and the neuronal environment resulting in cognitive decline and dementia. Therapeutic strategies that improve elimination of Abeta and other soluble metabolites from the brain may prevent cognitive decline in Alzheimer's disease.

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Figures

Figure 1

Figure 1

Perivascular pathways for the drainage of interstitial fluid (ISF), solutes, including amyloid‐β (Aβ), from the brain. Injection studies show that tracers diffuse through the extracellular spaces of the brain and enter basement membranes of capillaries to drain out of the brain along basement membranes in the tunica media of arteries. The drainage pathway is depicted here by the green lines and arrows. Basement membranes of the arterial endothelium and on the outer aspect of the arterial wall are devoid of tracer and are coloured blue. Endothelium is pink. From the results of the study by Carare et al. (15).

Figure 2

Figure 2

Amyloid angiopathy involving capillaries in Alzheimer's disease. Amyloid‐β (Aβ) is deposited in the basement membranes of cerebral capillaries. A. Normal capillary showing collagen IV (brown) in the basement membrane. B. Aβ (brown) in the basement membrane of a cerebral capillary. C. Small hemispherical “Drusen” of Aβ on the outer aspect of a capillary basement membrane laden with Aβ (brown). Immunohistochemistry for (A) collagen IV (Novocastra monoclonal antibody) (B) and (C) Aβ. Reproduced with permission from Preston et al(67). Bars = 10 µm.

Figure 3

Figure 3

Cerebral amyloid angiopathy with deposition of amyloid‐β (Aβ) in basement membranes of arteries. A. A normal leptomeningeal artery showing collagen IV (brown) in the basement membranes between the smooth muscle cells in the tunica media. Nuclei of the smooth muscle cells are stained blue. B. Tangential section through a leptomeningeal artery showing Aβ in the basement membranes of the tunica media. Immunohistochemistry for (A) collagen IV (Novocastra monoclonal antibody) (B) Aβ (Dako pan‐Aβ monoclonal antibody) Bars = 20 µm.

Figure 4

Figure 4

Cerebral amyloid angiopathy in smear preparations. A. A capillary loop (cap) with amyloid in its basement membrane (green) and a sheath of amyloid fibers in the surrounding brain. B. An artery with plates of amyloid (green) in the wall that appear to have been shattered during the preparation of the smear. A and B stained by thioflavin S. Confocal images. Reproduced with permission from Preston et al(67).

Figure 5

Figure 5

Loss of collagen IV in association with deposition of amyloid in the walls of arteries and capillaries in cerebral amyloid angiopathy (84) . A and B are from the same microscope field. A. Cerebral cortex stained only for collagen IV (black) showing focal loss of collagen IV from capillary (*, upper arrow) and artery (*, lower arrow) walls. B. The same vessels (* and arrows) show amyloid (green) replacing collagen IV in capillary and artery walls. The endothelial and outer basement membranes in the artery wall are selectively preserved and spared from amyloid deposits. Erythrocytes within vessel lumina are yellow. Immunohistochemistry for collagen IV (Novocastra monoclonal antibody), counterstained with Congo red for amyloid that appears green in this confocal hybrid image. Bars = 40 µm in both illustrations.

Figure 6

Figure 6

Laminin is lost from regions of amyloid deposition in the walls of capillaries in cerebral amyloid angiopathy (84) . A and B are from the same microscope field. A. cerebral cortex stained only for laminin (black) showing focal loss of laminin from capillary walls (*). B. The same vessels show amyloid (green) replacing laminin in the capillary basement membranes (*). Erythrocytes within capillaries are yellow. Immunohistochemistry for laminin, (Novocastra monoclonal antibody) counterstained with Congo red for amyloid that appears green in this confocal hybrid image. Bars = 40 µm in both illustrations.

Figure 7

Figure 7

Fibronectin is increased adjacent to regions of amyloid deposition in the walls of capillaries in cerebral amyloid angiopathy (84) . A and B are from the same microscope field. A. Cerebral cortex showing an increase in fibronectin (black) in the brain parenchyma around capillaries (*). B. The same vessels show amyloid (green) in association with the increase in fibronectin (*). Erythrocytes within vessel lumina are yellow. Immunohistochemistry for fibronectin (Novocastra monoclonal antibody), counterstained with Congo red for amyloid that appears green in this confocal hybrid image. Bars = 40 µm in both illustrations.

Figure 8

Figure 8

Failure of Elimination of amyloid‐β (Aβ) from the brain in Alzheimer's disease. A. In the normal young brain, Aβ is produced by neurons and other cells, diffuses through the extracellular spaces and is either degraded by neprilysin and insulin‐degrading enzyme (IDE) or absorbed into the blood via lipoprotein receptor‐related protein (LRP)‐1 mediated mechanisms. Some Aβ also drains with interstitial fluid along perivascular pathways in the walls of capillaries and arteries and a small proportion may diffuse toward the surface of the brain. B. With age disposal of Aβ by neprilysin, IDE and LRP‐1 mediated mechanisms fails and more Aβ is diverted to the perivascular drainage pathways. C. As arteries stiffen with age, perivascular drainage of Aβ becomes less efficient and ultimately fails because of blockage of the pathways by deposits of amyloid fibrils—cerebral amyloid angiopathy (CAA). Insoluble Aβ is deposited as plaques in the brain parenchyma and this interferes with diffusion of Aβ and other solutes through the extracellular spaces. Eventually, perivascular drainage fails and levels of soluble Aβ and other soluble metabolites in the brain rise and disturb homeostasis of the neuronal environment, resulting in neuronal malfunction, cognitive decline and dementia.

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