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Regular Articles |
From the Department of Neuropathology,*
University of
Southampton Medical School, Southampton General Hospital, Southampton,
United Kingdom, and Haldeman Laboratory for Alzheimer Disease
Research,
Sun Health Research Institute, Sun
City, Arizona
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There is now firm evidence that ISF from the brain drains to regional cervical lymph nodes in a range of species from rodents to sheep.4-6 Injections of tracers into the rat brain show that ISF drains along perivascular spaces around intracortical and leptomeningeal arteries; these channels eventually connect with nasal lymphatics at the cribriform plate of the ethmoid bone.4,7-9 The immunological significance of ISF drainage to cervical lymph nodes is emphasized by experiments in the rat showing that cervical lymphadenectomy reduces both B-cell immune reactions to antigens draining from the brain10,11 and T cell-mediated immune responses in the brain.12-14
Periarterial pathways, homologous with ISF drainage pathways in the rat, have been identified by histological and ultrastructural studies in the human brain.15-18 In the human cerebral cortex, periarterial spaces are encompassed by an outer sheath of leptomeningeal cells derived from the pia mater, and these spaces are in direct continuity with perivascular spaces around arteries in the subarachnoid space.15,17 In the basal ganglia, the arrangement is slightly different, as periarterial spaces are lined both on the inner and the outer aspects by layers of leptomeninges; however, the periarterial spaces within the brain are still in continuity with the perivascular spaces of leptomeningeal arteries.18 No such well defined continuity of intracortical and leptomeningeal perivascular spaces has been observed in relation to veins.15 Reports of glioblastoma metastasizing from the brain to cervical lymph nodes19 suggest that they may act as regional lymph nodes for the brain in humans as in other mammals.
Evidence that smooth muscle cells are a source of vascular amyloid1,20 derives mainly from the observations that they contain ß-amyloid precursor protein (APP) fragments21 and that they lie immediately adjacent to vascular Aß deposits. However, there are a number of problems with accepting that smooth muscle cells are the sole source of Aß in CAA. First, CAA is strictly confined to the central nervous system in AD, and extracranial vessels are free of Aß deposits,3 but there is little evidence that smooth muscle cells in extracranial arteries differ from intracranial arteries in terms of APP metabolism.3 Second, if Aß were produced by smooth muscle cells, early deposits of amyloid would be located throughout the tunica media, rather than in the adventitia and outer media.20-22 Third, if vascular smooth muscle cells were the only or major source of Aß, it would be expected that the larger arteries would be more prone to CAA, as they contain more smooth muscle cells, but, in fact, they are less severely involved than the smaller arteries.3
In the present study to test the hypothesis that Aß is deposited in periarterial ISF drainage pathways of the brain in AD, we use both biochemical and histological methods. Biochemical techniques are used to show that there is a pool of soluble Aß in non-AD cerebral cortex, which is presumably eliminated continuously from the normal brain. Qualitative and quantitative histological and immunohistochemical techniques are used to demonstrate 1) that there is a correlation between the presence of Aß senile plaques in the brain and amyloid angiopathy in AD; 2) that insoluble Aß accumulates selectively around small arteries in the brain and leptomeninges with relative sparing of large arteries and veins, suggesting that deposition of Aß occurs in drainage pathways nearest the site of origin of Aß from the brain; and 3) that small and possibly the earliest deposits of Aß in the walls of leptomeningeal arteries occur at the site of putative ISF fluid drainage pathways in the adventitia, and that only later does Aß accumulate in the tunica media.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Biochemical quantitation of soluble Aß was performed on cerebral
cortex from six brains of clinically nondemented control cases without
a history of neurological disease (average age, 79 years; range, 69–92
years) selected from the Sun Health Research Institute brain bank. All
six cases had a 
3/3 apolipoprotein E (ApoE) genotype. On
histological (thioflavin S and Campbell-Zwitzer stains) and
immunocytochemical (4G8, 10D5, and ubiquitin antibodies) examination,
these brains showed no visible deposits of amyloid in the parenchyma or
in the vasculature and no neurofibrillary tangles. Quantitative and
qualitative studies of senile plaques and CAA were performed on 17
formalin-fixed AD brains; 7 were from the Sun Health Research Institute
brain bank, and 10 were from the Neuropathology Laboratory, University
of Southampton.
Tris-hydroxymethyl aminomethane (Tris), ethylenediaminetetraacetic acid, leupeptin, pepstatin, phenylmethylsulfonyl fluoride, phenanthroline, benzamidine, and thioflavin S were from Sigma Chemical Co. (St. Louis, MO). Gentamicin sulfate, amphotericin B, hydrochloric acid, and formic acid were obtained from Fluka Chemie AG (Buchs, Switzerland). On all occasions, formic acid was glass distilled in our laboratory before use. Antibody 4G8 (against Aß17–24) was obtained from Senetek (Maryland Heights, MO) and was labeled with europium according to the manufacturer's procedure (Wallac Inc., Gaithersburg, MD). Eu and enhancement solution were from Delfia (Wallac, Inc.). Polyclonal antibodies R163 and R165 specifically raised against Aß40 and Aß42, respectively, were obtained from Dr. P. Mehta of the New York State Institute for Brain Research (Staten Island, NY). These antibodies do not exhibit cross-reactivity between each other up to 50 ng/ml. For immunocytochemistry on paraffin sections, an antibody raised against Aß1-39/42 was kindly donated by Dr. C. Wischik of the MRC Laboratory for Molecular Biology (Cambridge, UK).
Europium Immunoassay of Aß Peptides
Cerebral cortex (0.8 g) from the superior frontal gyrus was carefully separated from the underlying white matter. The tissue was minced into fine pieces and, to remove unwanted blood, rinsed three times with 5 ml of protease inhibitor buffer (20 mmol/L Tris-HCl, pH 8.5, 3 mmol/L ethylenediaminetetraacetic acid, 500 µg/L leupeptin, 700 µg/L pepstatin, 35 mg/L phenylmethylsulfonyl fluoride, 100 mg/L 1,10 phenanthroline, 100 mg/L benzamidine, 50 mg/L gentamicin sulfate, and 250 µg/L amphotericin B). The tissue was thoroughly homogenized with a motorized Duall tissue grinder (100 µm clearance) in the presence of 3 ml of the above buffer. The brain homogenates, 4 ml per sample, were spun at 100,000 x g for 1 hour at 4°C. The supernatants and pellets were collected and stored separately. For Aß quantitation, polyclonal antibodies R163 and R165 were coated to the wells of microtiter plates and used as the capture antibodies. Bovine serum albumin (1%) in TTBS (0.05% Tween in 20 mmol/L Tris-HCl and 0.5 mol/L NaCl, pH 7.4) was used as blocking solution. One hundred µl of the supernatant or of Aß standards was applied to the wells and allowed to stand at room temperature for 2 hours on a rocking platform. The unbound materials were removed by washing the plate three times with TTBS. Europium-labeled 4G8 was added to the wells and incubated for 2 hours followed by four washes with TTBS and two washes with deionized water. Finally, the Eu-enhancement solution was added to each well and the plates were read in a fluorimeter using excitation and emission wavelengths of 320 and 615 nm, respectively. The values, obtained from triplicated wells, were calculated based on standard curves generated on each plate.
Quantitation of Amyloid Angiopathy in Relation to Amyloid Plaque Density
A total of 24 blocks of cerebral cortex were taken from 3 AD brains. From each brain, two blocks were taken from frontal, temporal, parietal, and occipital lobes. The leptomeningeal vessels were carefully stripped from the surface of the blocks of brain, stained free floating with thioflavin S, and spread onto glass slides for observation in either ultraviolet light (395 nm) or visible light (450 nm). Aß deposition in leptomeningeal vessels was recorded on a semiquantitative scale in these preparations: -, no evidence of amyloid; +, moderate amyloid deposition and no aneurysm formation on the vessels; ++, clear evidence of amyloid angiopathy and some vessels with occasional aneurysm formation; +++, obvious amyloid angiopathy in the majority of vessels; and ++++, virtually all vessels showing evidence of amyloid angiopathy and multiple aneurysms.
Blocks of cerebral cortex from which the leptomeninges had been stripped were dehydrated and embedded in paraffin, and 5-µm sections were stained with thioflavin S. The total number of thioflavin S-positive amyloid plaques in the gray matter on each slide (mean area, 30 mm2) was counted and the number of plaques per unit area of cortex (plaque density) was estimated using Color Vision version 1.7.4.A on an Apple Macintosh Quadra 700 computer. The semiquantitative estimation of thioflavin S-stained amyloid deposition in the leptomeningeal vessels was compared with the plaque density in the underlying cortex.
Quantitation of Amyloid According to Vessel Type
A total of 56 blocks of cerebral cortex were taken from seven AD brains. Two blocks were taken from the frontal, temporal, parietal, and occipital cortex of each brain. Leptomeningeal vessels were carefully stripped from the brain's surface and histologically processed, sectioned (5 µm), and stained with thioflavin S. A total of 681 arteries and 352 veins were investigated. For immunocytochemical studies, 5-µm sections were stained with an antibody against Aß1-39/42. The number of diffuse and fibrillar plaques in the entire cortical area of each section was counted using a Leitz Laborlux K light microscope with a x20 objective lens. The area of gray matter was measured in serial sections stained with the hematoxylin van Gieson technique using enhanced image analysis. Cortical plaque densities were calculated for each plaque type by dividing the relevant plaque count by the area of gray matter analyzed.
Assessment of amyloid angiopathy was performed on paraffin sections of leptomeningeal vessels stained with thioflavin S and examined in ultraviolet light under a fluorescence microscope. All vessels that had been sectioned transversely (ie, at no point was the maximum diameter more than twice the minimum diameter) were assessed. The diameter of each vessel was recorded using an eyepiece graticule. Identification of vessels as arteries and veins depended on the ratio of wall thickness to lumen diameter and the presence or not of an elastic lamina.
Qualitative Histology
Five brains from patients with AD were used for the isolation of intracortical and leptomeningeal vessels for qualitative assessment of the deposition of amyloid. Cerebral cortex from all four cerebral lobes were cut into approximately 1-cm3 pieces and lysed in 20 volumes of 15% sodium dodecyl sulfate, prepared in 50 mmol/L Tris-HCl (pH 7.5) buffer containing 5 mmol/L ethylenediaminetetraacetic acid. After 72 hours of continuous stirring and two changes of sodium dodecyl sulfate, the remaining tufts of blood vessels were filtered out, washed with buffer, and stained with thioflavin S. Leptomeningeal vessels, stripped from the surface of cerebral cortex, were spread on glass slides, air dried, stained with thioflavin S, and examined in a fluorescence microscope by phase contrast and by Nomarski optics. Selected vessels were examined with a Leica TCS4D Krypton-Argon confocal laser scanning microscope; the image of thioflavin S fluorescence under light of 490-nm wavelength was digitally captured in 64 planes, allowing three-dimensional reconstruction.
Electron Microscopy
Cerebral cortex from three AD brains was taken fresh postmortem, fixed in glutaraldehyde, postfixed in osmium, stained with uranyl acetate, and embedded in Epon Araldite resin for electron microscopy. Thin sections of cerebral cortex were stained with lead citrate and examined in a Phillips 400 transmission electron microscope.
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Results |
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In the six brains from clinically nondemented control cases, Europium immunoassay demonstrated an average value of water-soluble Aß of 2.75 ng/g of cerebral cortex (range, 0.2 to 8.6 ng/g). In only one instance was the level of water-soluble Aß below the detection limit of 0.1 ng/g. Although this level is in contrast to the average of 36.8 ng/g of water-soluble Aß in AD brains that we have previously demonstrated,23 it nevertheless shows that Aß is present in a water-soluble pool of non-AD brain tissue without visible deposits of Aß.
Correlation between CAA and Plaque Density
Detailed examination of thioflavin S-stained sections of brain and
overlying meninges stripped from the cerebral cortex showed that
amyloid angiopathy did not occur in the absence of amyloid deposition
in senile plaques in the underlying cortex. A positive correlation
between the degree of amyloid angiopathy and the deposits of fibrillar
amyloid in the subjacent cortex was observed up to the +++ levels of
CAA (P < 0.05; Table 1
). However, this increase was not
maintained with the grade ++++ CAA.
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Accumulation of Amyloid in Walls of Arteries and Veins of Different Calibre
In paraffin sections of leptomeninges stained with thioflavin S,
amyloid deposition was detected in the walls of 20.2% of 681 arteries
and in 4.5% of 352 veins (Table 2)
. This
represents a ratio of 5:1 for amyloid deposition in the walls of
arteries compared with veins. Deposition of amyloid in arterial walls
was observed in 24.7% of small leptomeningeal arteries (less than 60
µm in diameter) and in 11.2% of larger arteries (60 to 300 µm in
diameter), giving a ratio of 2:1 between the two groups. No difference
in the degree of amyloid deposition between veins of large and small
diameter was seen. Amyloid deposition in intracortical vessels followed
a similar pattern to that observed in the leptomeninges with arteries
predominating over veins.
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Treatment of cerebral cortex from brains of patients with AD with
10% SDS resulted in isolation of the blood vessels; vessel basement
membranes, perivascular connective tissue, and amyloid deposits were
preserved, because these structures are insoluble in the detergent.
Thioflavin S-stained preparations revealed globular deposits of amyloid
arranged like beads along small blood vessels (Figure 1A)
with linear deposits of amyloid
outlining the intervening blood vessel walls (Figure 1B)
. Arteries of
larger diameter within the cortex contained band-like deposits of
amyloid distributed transversely, or circumferentially around the
vessel wall (Figure 1C)
. Immunocytochemistry for Aß in paraffin
sections showed that the band-like disposition of the amyloid was due
to the interposition of smooth muscle cells between the Aß deposits
(Figure 1D)
; preserved smooth muscle cells were clearly seen surrounded
by Aß. At the surface of the brain, Aß was observed in the walls of
arteries as they penetrated the cortex, in leptomeningeal arteries, and
deposited at the glia limitans (Figure 1D)
.
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. In other arteries, amyloid was
deposited between smooth muscle cells with considerable disruption of
the vessel wall (Figure 2B)
. Thin profiles of smooth muscle were
observed within the amyloid, and smooth muscle cells in the subintimal
region appeared to be better preserved than those in the outer aspects
of the wall (Figure 2B)
.
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The pattern of Aß deposits in the walls of leptomeningeal
arteries was similar to that in the larger intracortical arteries.
Bands of amyloid were disposed intermittently along the length of
arteries, often concentrated distal to bifurcations (Figure 3A)
. In areas where amyloid deposition
was heavy, aneurysm formation occurred either as fusiform expansion of
the vessel (Figure 3A)
or as more saccular extrusions (Figure 3B)
. In
some instances, the microaneurysms were surrounded by fine deposits of
hemosiderin, suggesting past hemorrhage.
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. Small deposits of Aß in the larger leptomeningeal
arteries were always at the periphery of the tunica media where it
meets the adventitia close to the periarterial space (Figure 3, C and D)
. Early deposits of amyloid were never observed in the vicinity of
the endothelium or the internal elastic lamina. As the amount of
amyloid increased, deposits involved the outer part of the media in
addition to the more peripheral regions of the artery wall (Figure 3, E and F)
. Occasionally, small deposits of amyloid were present in the
connective tissue of the arachnoid mater (Figure 3D)
, but they were
always extremely small in comparison with deposits in arterial walls.
Deposition of amyloid in leptomeningeal veins was much less common than
in arteries (Table 2)
and very small in amount. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Figure 4
summarizes diagrammatically the
distribution of Aß in CAA emphasized in the present study. Aß forms
globular and linear deposits in association with the walls of small
intracortical vessels and band-like deposits in the walls of larger
arteries in the cortex. In the leptomeninges, it is the small arteries
that are most severely affected by Aß deposition; larger arteries are
relatively or completely spared, and veins show only minor Aß
deposition. The small, and probably early, deposits of Aß in
leptomeningeal artery walls are in the adventitia and thus at the site
of the putative periarterial drainage pathways for ISF from the brain.
It is unclear, as yet, whether such drainage pathways in humans have
the same immunological significance as those in other
species4,13,14
or to what extent ISF leaks into the
cerebrospinal fluid (CSF) of the subarachnoid space.15
The
high concentration of Aß in perivascular compartments around arteries
and the relatively small amounts of Aß in the arachnoid do suggest,
however, that substantial amounts of Aß remain within perivascular
ISF drainage pathways.
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In relation to CAA, the present study has shown that Aß in AD brains accumulates around arteries five times more commonly than around veins, and that small arteries (<60µm diameter) in the leptomeninges are more severely involved than the larger arteries (60 to 300 µm in diameter). There is no selectivity of large or small veins in relation to the very small amount of Aß deposited within their walls. Stainable fibrillar amyloid does not appear to accumulate within the walls of cerebral or leptomeningeal arteries larger than 500 µm in diameter. In general, therefore, there is an inverse gradient in the accumulation of Aß related to the caliber of the artery; the larger the size of the artery, the smaller the amount of stainable amyloid. However, Aß1-40 is detectable biochemically in the walls of the middle cerebral and basilar arteries even in young adults,3 which suggests that soluble amyloid is in the perivascular spaces of even the largest arteries. Amyloid angiopathy was not observed in the absence of amyloid plaques in the underlying cortex, and a linear correlation between the severity of the CAA and the number of Aß plaques in the underlying cortex was seen in four out of seven of the cases examined. All of these observations support the hypothesis that Aß is eliminated from the brain along periarterial drainage pathways and accumulates in such pathways in CAA. As yet, it is not clear how ISF and Aß in perivascular drainage compartments finally leave the cranial cavity and to which lymph nodes they drain.
Various hypotheses have been advanced to explain the origin and distribution of Aß in blood vessel walls, and a number of mechanisms may contribute to CAA.28
Hematogenous Origin
Blood-borne amyloid is known to be associated with angiopathy, as with the immunoglobulin amyloid of multiple myeloma. As the APP is normally expressed in platelets29 and the blood levels of APP are increased in Down's syndrome patients,30 it is possible that APP in the blood may be subsequently deposited as Aß in blood vessel walls. However, the present study and previous reports show that Aß deposits in arterial walls are initially confined to the adventitia and outer media of the vessel wall rather than to the vicinity of the endothelium.1,20-22 This abluminal site of deposition, in addition to the restriction of CAA to central nervous system vessels,3 argues against a hematogenous origin for the amyloid. In blood-borne amyloidoses, such as multiple myeloma, arteries are affected throughout the body, whereas there is only one report of trace amounts of Aß outside the central nervous system in AD.31 In other amyloidoses, in which the amyloid precursor is known to be blood borne, amyloid is found in the walls of both arteries and veins.32
Origin from CSF
The CSF could be a source of amyloid in CAA, particularly as Aß is detected in CSF of normal and AD individuals,33 and it has been suggested that amyloid is deposited in leptomeningeal vessels via the CSF in the transthyretin amyloidosis.34 However, amyloid is much more frequently deposited in arteries than in veins, as has been shown in this and other studies,22,28 and yet both types of vessel are exposed to the CSF. In addition, small arteries in the subarachnoid space are affected more commonly and more severely than larger arteries in the same location, yet they are all surrounded by CSF. Small intracortical arteries and capillaries are major sites for Aß deposition, but they are at some distance from the CSF and separated from it by the pia mater.35-37 These features argue strongly against the CSF in the subarachnoid space being the main source of Aß in CAA.
Smooth Muscle Cells as a Source of Aß
The relationships between the drainage of Aß from brain tissue into the perivascular spaces in AD and the local production or uptake of amyloid by smooth muscle cells are a matter for conjecture. Aß1-40 and Aß1-42 are rapidly internalized by cultured human and canine smooth muscle cells derived from leptomeningeal vessels. Internalization appears to be in association with ApoE.38 It is possible that the deposition of parenchymal amyloid in blood vessel walls may also stimulate the local production of Aß, as the major species of Aß that accumulate within the brain differ from those in vessel walls. Aß in senile plaques consists mainly of the 1-42 species39,40 whereas vascular amyloid is mostly composed of 1-40 species.40,41 Aß1-40 draining from the brain may be supplemented from Aß1-40 produced by smooth muscle cells as part of a stress response to the accumulation of Aß1-42, particularly as it has been shown that smooth muscle cells, when stimulated by exogenous Aß, are capable of producing APP and Aß.42
Cerebral Cortex as a Source of Amyloid
The relative proportions of Aß1-42 to Aß1-40 are higher in cortical vessels than in leptomeningeal vessels,40 which is consistent with neurons being the source of Aß1-42 and the vasculature producing Aß1-40 peptide in response. Cortical vessels are closer to the source of Aß1-42 than leptomeningeal vessels and hence show deposition of proportionately more Aß1-42. More convincing, however, is the observation that, whereas some vascular amyloid deposits in vessels are solely composed of Aß1-42, deposits consisting of Aß1-40 alone have not been recorded.3 In hereditary cerebral hemorrhage with amyloidosis, Dutch type,43 fibrillar Aß1-40 is deposited in cortical and leptomeningeal vessel walls. In this disease, the Aß in the neuropil is mainly of the diffuse, nonfibrillar, amorphous type, whereas fibrillar Aß is only present in the glia limitans around the cortical vessels.44 This suggests that Aß1-42, derived from the brain, may be the initial amyloid to be deposited in vessel walls and that it entraps the more soluble Aß1-40, which normally drains from the brain along perivascular spaces more easily than Aß1-42. Soluble Aß could be sequestered by the basal laminae of vascular endothelial cells, pericytes, and/or smooth muscle cells; such basal laminae are rich in proteoglycans for which Aß has a high affinity.45 Finally, the solubility properties of Aß1-40 may permit this molecule to diffuse for larger distances than the less soluble Aß1-42, resulting in an increased proportion of Aß1-40 deposited around leptomeningeal vessels.
In conclusion, evidence from the pattern of distribution of Aß in AD
suggests that accumulation of Aß in ISF drainage pathways contributes
significantly to CAA46
(Figure 4)
. Similar criteria may be
applicable to the amyloid angiopathy observed in other pathologies such
as prion diseases47
and cystatin C
amyloidosis.48
Amyloid, particularly Aß1-40 peptide, is
present in non-AD brains and has been detected in the walls of the
large arteries of the circle of Willis in young adults.3
These findings support the concept that, under normal circumstances,
the brain eliminates Aß peptides via periarterial ISF fluid drainage
pathways. Aß may be deposited within vessel walls, either through
increased production of insoluble Aß1-42, through the obstruction of
ISF drainage pathways, or because of failure of solubility factors.
Such deposition in turn may induce Aß production by smooth muscle
cells with further obstruction of drainage pathways and further
accumulation of Aß within the cerebral cortex and its vasculature in
AD.
Consideration of possible solubility factors involved in the transport of Aß along periarterial fluid drainage pathways may yield opportunities for therapeutically enhancing the elimination of Aß from the brain. ApoE, for example, may act as a transport molecule for mobilization of Aß1-40 in the ISF.49 Because the predominant species of vascular amyloid is Aß1-40, transport of Aß from the brain along perivascular ISF drainage pathways may be defective in individuals with particular ApoE alleles, resulting in the accumulation of amyloid peptides in senile plaques and arterial walls. Compensating for ApoE or other solubility defects may reduce the deposition of amyloid in the brain.
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Footnotes |
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Supported in part by NIH grant AG-11925 (to AER) and by the Wessex Medical Trust Brain Fund and the David Gibson Fund (to ROW). MH is a recipient of VJ Chapman Research Fellowship from the New Zealand Neurological Foundation.
Accepted for publication June 5, 1998.
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