Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease

Abstract

Cerebral amyloid angiopathy in Alzheimer's disease is characterized by deposition of amyloid beta (Abeta) in cortical and leptomeningeal vessel walls. Although it has been suggested that Abeta is derived from vascular smooth muscle, deposition of Abeta is not seen in larger cerebral vessel walls nor in extracranial vessels. In the present study, we examine evidence for the hypothesis that Abeta is deposited in periarterial interstitial fluid drainage pathways of the brain in Alzheimer's disease and that this contributes significantly to cerebral amyloid angiopathy. There is firm evidence in animals for drainage of interstitial fluid from the brain to cervical lymph nodes along periarterial spaces; similar periarterial channels exist in humans. Biochemical study of 6 brains without Alzheimer's disease revealed a pool of soluble Abeta in the cortex. Histology and immunocytochemistry of 17 brains with Alzheimer's disease showed that Abeta accumulates five times more frequently around arteries than around veins, with selective involvement of smaller arteries. Initial deposits of Abeta occur at the periphery of arteries at the site of the putative interstitial fluid drainage pathways. These observations support the hypothesis that Abeta is deposited in periarterial interstitial fluid drainage pathways of the brain and contributes significantly to cerebral amyloid angiopathy in Alzheimer's disease.

Figure 1.

CAA of cortical vessels in AD. Aβ deposits associated with intracortical vessels, isolated by 10% sodium dodecyl sulfate treatment, stained by thioflavin S, and viewed in a fluorescence microscope (A to C). A: Globular deposits of amyloid are arranged along a small intracortical blood vessel. B: Linear deposits of amyloid (arrow) outline the wall of a small intracortical blood vessel between the globular deposits. C: Intracortical arteries showing transverse bands of amyloid deposition in the vessel walls. D: Paraffin section stained by immunocytochemistry for Aβ. Two leptomeningeal arteries can be seen on the right of the picture. In the larger vessel (top right), Aβ is deposited in the adventitial region and the media is intact. The smaller vessel sends a branch into the cortex; smooth muscle cells in the media of this artery are surrounded by amyloid deposits producing a band-like appearance similar to that seen in thioflavin S preparations. Amyloid is also present at the glia limitans on the surface of the cortex (arrow).

Figure 2.

CAA of cortical vessels in AD. Transmission electron micrographs of intracortical arteries showing the pattern of deposition of amyloid in perivascular spaces and in the media. A: The perivascular space of this small intracortical artery is expanded by darkly stained wisps of amyloid, separating the glia limitans (arrows, top right, and bottom left) from the smooth muscle cells of the intact arterial media. Bar = 5 μm. B: Artery in which amyloid has been deposited within the perivascular space and between smooth muscle cells in the media. Glia limitans (arrowheads). Deposition of amyloid is heavier in the outer aspect of the media than in the inner aspects, where the smooth muscle cells remain better preserved (arrow). Bar = 5 μm.

Figure 3.

CAA of leptomeningeal arteries in AD. A: Isolated leptomeningeal artery showing heavy deposition of amyloid as transverse bands within its walls, associated with aneurysmal dilatation. Confocal microscopy: three-dimensional reconstruction, thioflavin S stain. B: Isolated leptomeningeal vessels viewed by phase-contrast microscopy showing a fusiform microaneurysm (left arrow) and a saccular microaneurysm (right arrow). C to F: Patterns of amyloid deposition in paraffin sections of leptomeningeal vessels and arachnoid stained with thioflavin S. C: Some smaller arteries show amyloid deposition throughout the thickness of their walls (left arrow), whereas other small vessels show complete absence of amyloid (right arrow). In the larger vessel, amyloid is deposited as a linear streak (middle arrow) in the adventitia and perivascular space. D: Leptomeningeal artery with a small streak of amyloid deposited at the junction of the media and adventitia (right arrow). The associated arachnoid mater also contains small streaks of amyloid (left arrow). E: Part of the wall of a leptomeningeal artery showing a linear circumferential deposit of amyloid at the junction of the adventitia and the media (arrow). F: Linear deposit of amyloid (arrow) in the wall of a leptomeningeal artery; the deposit is mostly in the adventitia near the perivascular space but also extends into the outer media.

Figure 4.

Diagram summarizing the pattern of the distribution of amyloid in CAA associated with AD. a: Aβ accumulates as globules or linear deposits in the perivascular spaces of small intracortical blood vessels or as transverse bands in the walls of larger intracortical arteries and in smaller leptomeningeal arteries. The severity of amyloid angiopathy decreases with increasing size of the artery, suggesting that Aβ is precipitated to a greater extent in the initial portions of the pathways draining ISF from the brain. b: With increasing deposition, Aβ surrounds smooth muscle cells in the media. c: Eventually, smooth muscle cells are lost and aneurysms may form.