Acta Neuropathol (1992) 84:117 - 127

kta Heuropathologh',a (~) Springer-Verlag1992

Regular papers Ultrastructural studies of the cells forming amyloid in the cortical vessel wall in Alzheimer's disease* H. M. Wisniewski 1, J. WegieP, K. C. Wang 1, and B. Lach 2 i Department of Pathological Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA 2 Anatomical Pathology, Laboratory Medicine, Ottawa Civic Hospital, 1053 Carling Avenue, Ottawa, Ontario KIY 4E9, Canada Received November 11, 1991/Revised, accepted February 11, 1992

Summary. Ultrastructural studies of serial sections of the vessels with amyloid deposits in the brain cortex of patients with Alzheimer's disease showed that cells in the position of pericytes - perivascular cells - and perivascular microglial cells are producers of amyloid fibrils in the vascular wall. Three types of changes from normal are distinguishable in the vessel wall: (1) semicircular or circular thickening of vascular wall containing a large amount of amorphous material and various number of amyloid fibrils, (2) tuberous amyloid deposits containing both amorphous material and amyloid fibrils, some of the fibrils being arranged in strata and others arranged radially, and (3) amyloid star composed of a predominantly radial arrangement of bundles of amyloid fibrils and a less prominent amorphous component. A mixture of amorphous material and amyloid fibrils is present in cell membrane envaginations of perivascular cells, and occasionally perivascular microglial cells. Bundles of amyloid fibrils are found in altered cisternae of the endoplasmic reticulum and in the channels confluent with the infoldings of the plasma membrane of perivascular microglial cells. The amyloid deposition in the wall of the vessel causes degeneration of endothelial cells and the reduction of, and in some vessels obliteration of, the vessel lumen. In areas affected by amyloid angiopathy, extensive degeneration both of the neuropil and of neurons was observed. These changes were accompanied by astrogliosis. This study demonstrates similarities in amyloid formation in amyloid angiopathy and in ~-amyloid plaques in the neuropil and suggests that cells of the mononuclear phagocyte system of the brain (perivascular cells and perivascular microglia) are engaged in amyloid fibril formation.

* Supported in part by funds from the New York State Office of Mental Retardation and Developmental Disabilities and a grant from the National Institutes of Health, National Institute of Aging No. POt-AGO-4220 Correspondence to: H. M. Wisniewski (address see above)

Key words: Alzheimer disease - Amyloid angiopathy Pericytes - Microglia - Ultrastructure

Cerebrovascular amyloidosis occurs as a part of Alzheimer's disease (AD) [6, 7, 10, 1'7, 18, 20, 26, 28, 32, 37, 38]. This change may also arise as a sporadic idiopathic disorder [2, 35], either in association with an autosomal dominant form of amyloidosis (Dutch type) [36] or in the area of cerebrovascular malformations [14, 30]. Meningeal vessels may also be affected by this process [27, 37]. The deposition of ~-amyloid fibrils in the walls of blood vessels is observed also in aged monkeys [3, 42], especially in squirrel monkeys [40], and in dogs [16, 29, 39, 44, 46]. Ultrastructural studies of neuritic plaques in humans and animals have shown that microglia/macrophages are associated with deposits of amyloid fibrils [42, 43]. Our previous studies [41, 45, 47] have revealed that microglial cells manufacture amyloid fibrils of ~-amyloid plaques in the neuropil. The purposes of this ultrastructural study were to identify (1) the cells that make amyloid in the wall of the cerebral vessels, (2) the ultrastructural characteristics of the cellular compartments involved in amyloid fibril formation, and (3) the pathological changes in the vessels caused by amyloid deposits.

Material and methods Six cortical biopsies of patients with AD were examined by light and electron microscopy.Tissue was fixed in 3 % glutaraldehyde in 0.1 M phosphate buffer, pH 7.4, and posffixed in 1% osmium tetroxide in Sorensen's phosphate buffer. After dehydration, the material was embedded in Epon. Blocks from the brain of a 73-year-old male with heavy amyloid angiopathy were selected for this study, using serial sections. Tissue blocks were cut in semithin (0.5 ~tm) and ultrathin (0.06 ~tm)sections. Semithin sections were stained with toluidine blue. Ultrathin sections were collected on copper grids and stained with uranyl acetate and lead citrate.

119 Fig. 1. Amyloid pole of perivascular cell (P) located in the position of a pericyte and totally enclosed within basal lamina. Amyloid fibrils (A) are embedded in amorphous material in the cavity formed by perivascular cell processes. Shallow infoldings of cell membrane filled with amyloid fibrils (arrows). Endothelial cells (E) and collapsed lumen of the vessel (L). Inset: Higher magnification of amyloid infoldings, x 14,500, inset • 42,000

ly arranged amyloid fibrils (Fig. 6). However, unlike the star in the classical plaque, which is always round, the perivascular star shows an indentation where it rests on the vessel wall. In the area of the indentation, where the amyloid fibrils infiltrate the basal lamina, the bundles of amyloid fibrils follow the stratified pattern of basal lamina elements. On longitudinal sections, some vessels show multiple confluent stars (Fig. 7).

Results

Ultrastructural studies show that amyloid fibrils are in direct contact with perivascular cells located in the position of pericytes (Fig. 1), transitional forms of these cells whose body is partly within the perimeter and partly outside of the outer layer of the basal lamina (Fig. 2), and perivascular microglial cells (Fig. 3). The features common to all three types of cell are their polarity and their characteristic interface with amyloid deposits.

Semicircular and circular amyloid deposit The accumulation of amyloid fibrils and of a large amount of amorphous material is evident as a semicircular thickening of the vascular basement membrane (Fig. 4). Amyloid fibrils, embedded in amorphous material, form stratified aggregates in the wall of the affected vessel. In some vessels, mainly in larger cortical vessels, this type of amyloid deposits prevails.

Tuberous amyloid deposit In many vessels, focal, tuberous aggregates of amyloid fibrils are formed. In these profiles bundles of densely packed amyloid fibrils, arranged in radial and striatal fashion, are embedded in amorphous material. These profiles are located between perivascular cells (Fig. 5) and the endothelial cells.

Amyloid star deposit The large perivascular amyloid stars look like the stars in the classical plaques of the neuropil. At their periphery, they show the characteristic spike-like bundles of radial-

Fig. 2. Amyloid-making cell with long cytoplasmic process

enclosed within basal lamina (doublearrows) and the body outside the wall of the vessel has the features of both perivascular cell and perivascular microglial cell (PM). Shallow infoldings of the cell membrane and channels (arrow) are filled with amyloid fibrils and amorphous substance. Amyloid deposit in the vascular wall (A). Inset: Higher magnification of amyloid channels, x 5,800, inset x 10,000

Relationships of perivascular cells and perivascular microglia with amyloid deposits Perivascular microglial cells that form amyloid stars show elaborate cytoplasmic membrane infoldings and a labyrinth of distended endoplasmic reticulum (ER) membranes (Fig. 8). Sometimes, only one of the processes of the perivascular microglial cell participates in amyloid fibril formation. In areas where the perivascular cells located in the position of pericytes form semicircular or circular amyloid deposits, the surface of contact between the amyloid-making cells and the amyloid fibrils mixed with basal lamina elements is characterized by numerous shallow infoldings of the cell membrane filled with amyloid fibrils (Figs. 2, 5). In some areas, these infoldings appear to be in continuity with locally proliferated and slightly distended smooth E R membranes.

Pathology of vessels affected by amyloid fibril deposits In vessels with semicircular, circular, or tuberous amyloid deposits, the basal lamina is altered by the infiltration of amyloid fibrils and by an increased amount of structureless material. In these vessels, some endothelial cells show shrinkage and increased cytoplasmic density (dark endothelial cells; Fig. 5). There are also endothelial cells that are electron lucent, having increased volume and containing degenerative mitochondria (swollen endothelial ,cells; Fig. 9). In the majority of the affected vessels, the lumen is reduced. Vessels with amyloid stars, particularly those with multiple stars, show an advanced stage of endothelial cell and pericyte degeneration and appear to be occluded (Figs. 6, 7).

Relationship between vascular amyloid deposits and the neuropil In areas where the perivascular amyloid deposits contact the neuropil, they are generally surrounded, by astrocytic processes. The amyloid accumulated in the walls of the larger vessels as semicircular or circular deposits does not infiltrate the surrounding neuropil. However, in some areas, especially in vascular amyloid stars, wisps of amyloid fibrils are not covered by astrocytes. In these places, clusters of dystrophic and degenerative neurites are present (Fig. 10).

120

121 Fig. 3. Wide interface of perivascular microglial cell (M) with amyloid deposit (A) in the vascular wall. Numerous deep amyloid channels (arrows). Inset: Higher magnification of deep channels filled with dense bundles of amyloid fibrils. Direct contact of amyloid channels (double arrow) with smoothe endoplasmic reticulum (ser). • 8,700, inset • 17,400 Fig. 4. Semicircular thickening of the vascular basal lamina. Stratified aggregates of amyloid fibrils (A) embedded in amorphous material. Perivascular microglial cell (M). x 8,700

Neuronal and neuropil pathology in areas outside of the affected vessels Shrinkage of neuronal perikarya and formation of vacuoles within the E R and perinuclear envelope are seen frequently (Fig. 11). Mitochondria also are swollen and have disrupted membranes. The nuclei of the affected neurons have segregated and condensed nuclear chromatin and nucleolar material. Dystrophic and degenerative neurites are commonly seen.

In the neuropil, numerous clear and fibrous astrocytic processes are visible. Amyloid stars are covered by a thin mantle of astrocytic processes (Figs. 6, 7, 9). Groups of astrocytic cell bodies are also observed.

Discussion Our studies of the vessels affected by ~-amyloid fibril deposits revealed a broad spectrum of morphological forms of fibril arrangement, ranging from focal semicircular deposits to circular, tuberous deposits and fully developed amyloid stars. The amount of amyloid fibril deposit and the type of cell involved in formation of these fibrils appear to determine the final morphology of the deposits. When the perivascular cell is engaged in fibril formation, only one cytoplasmic pole, the one facing the endothelial cell, shows multiple vesicles filled with amyloid fibrils. These cytoplasmic vesicles are in close apposition to the smooth E R membranes of the perivascular cell. In areas where not many amyloid

Fig. 5. Tuberous amyloid deposit covered by perivascular cell processes (P). Bundles of amyloid fibrils arranged in striatal (s) and radial fashion (r) are embedded in amorphous material. Normal (arrow) and dark (two arrows) endothelial cell. • 8,700

122

Fig. 6. Perivascular amyloid star (A) attached to the obliterated vessel (V). The second vascular profile (VV) shows only minimal amyloid fibril infiltration (AA). Characteristic radial arrangement of bundles of amyloid fibrils in the star. Striatal distribution of amyloid fibrils in the place where amyloid fibrils infiltrate basal lamina. Mantle of astrocytie processes around the star (As). x 9,000

Fig. 7. Longitudinal section of obliterated vessel (V) surrounded by multiple confluent amyloid stars (A). Narrow rim of astrocytic processes (As) and one cluster of dystrophic neurites (dn). Microglial cell (M). x 3,250

Fig. 8. Newly formed amyloid fibrils appear in the smooth endoplasmic reticulum infoldings of the plasma membrane of perivascular microglial cell (M). • 25,200

(ser) and in the channels (arrow) confluent with the

Fig. 9. Edematous changes in endothelial cells (E) and diminished lumen (L) in a vessel with amyloid star (A). Narrow mantle of astrocytic processes (As) around the star and small interface of amyloid deposit with the process of microglial cell (M). • 8,700

Fig. I0. Cluster of dystrophic and degenerative neurites

(dn) in direct contact with amyloid wisps

(A). x 18,000

125

Fig. U . Degeneration of the neuron (N) with vacuolation of endoplasmic reticulum (er), perinuclear envelope (e) and mitochondria (m). Focal condensation of the chromatin and nucleolar material. Obliterated vessel (V) with amyloid star (A). Microglial

cell (M) with one process forming contact with amyloid deposit. The channels in the cytoplasm of microglial cell are filled with newly formed amyloid fibrils (arrow). • 9,000

126 fibrils have been made, the fibrils have infiltrated the basal lamina and are embedded in its matrix, which still retains laminar pattern. By and large, the semicircular deposits of amyloid are associated with perivascular cells; in the circular deposits, more than one perivascular cell participates in formation of amyloid fibrils. Perivascular cells and perivascular microglia are also observed to participate in formation of semicircular and circular amyloid deposits as well as tuberous deposits of amyloid fibrils. The perivascular microglia appear to be the only cells engaged in the formation of amyloid stars. The pole of these cells associated with the formation of the amyloid fibrils looks different from the perivascular cells totally or partially enclosed within the basal lamina. In the latter, as indicated above, very shallow vesicles filled with some amyloid fibrils are seen. The characteristic features of the perivascular microglia associated with the amyloid star are deep infoldings of the cellular membrane and distended E R channels filled with amyloid fibrils. The morphology of the amyloid-making pole of the perivascular microglial cell is very similar to that which we observed in the cells making amyloid fibrils in the classical and primitive plaques of the neuropil [41, 45, 47, 48]. In larger vessels, the semicircular and circular amyloid deposits do not infiltrate the surrounding neuropil. However, in precapillaries, vascular amyloid often infiltrates the neuropil, precipitating dystrophic and degenerative responses. In areas of amyloid stars, some of their *'spikes" are also seen to be in contact with neurites. In the neuropil surrounding the amyloid stars, a few aggregates of, or single, dystrophic neurites are seen. In this sample, none of the neurites contain paired helical filaments. The amyloid stars that are formed within the wall of the vessel and afterwards "grow" into the neuropil are always surrounded by a narrow rim of astrocytic processes. This configuration is in contrast to the stars of the classical plaques of the neuropil, whose surface is only partially covered by astrocytes and which show many wisps of amyloid fibrils infiltrating the neuropil [45].Tangential cuts of the perivascular amyloid stars, accompanied by minimal or no neuritic response, have a similar appearance to that of burned-out or amyloid plaques having a small number of degenerating and dystrophic neurites. Only reconstruction using serial sections allows classification the type of lesion. The amount of amyloid deposited had an impact on the endothelium and the lumen of the affected vessels. Many of the vessels with multiple amyloid stars were obliterated. Vessels with amyloid stars and tuberous amyloid deposits contained both degenerating endothelia and completely destroyed basal lamina.The extensive astrogliosis and the many neurons in various stages of degeneration seen in these areas, therefore, appear to be the result of ischemic changes. On the basis of changes somewhat similar to those described in this paper, Ishii [17, 18] and Miyakawa and coworkers [23-25] concluded that all plaques arise from the vessel wall. In our experience, as well as that of other investigators studying human and monkey brains [3, 4, 19, 21], only a part of plaques arises from the vessel wall.

However, the morphology of cells that are engaged in the formation of amyloid fibrils and the fact that their bodies lay in part under an external layer of vascular basal lamina and in part in the neuropil suggest that the microglia that make amyloid fibrils in the neuropil are derived from the vessel wall. Perivascular cells, which fit the morphological definition of pericytes in that they are also enclosed within the basal lamina of the vessels, probably represent a distinct population of resident brain macrophages, as indicated by their immunophenotype [12, 13, 33]. Perivascular cells enclosed within basal lamina of vessels and perivascular microglial cells are probably of bone marrow origin [1, 5, 15, 22]. In summary, on the basis of both our previous studies of the association between the microglia and the amyloid fibril deposits in the various types of ~ and prion protein plaques and the present ultrastructural analysis of the cells making amyloid fibrils in the vessel wall, we conclude that certain brain microglia and perivascular cells are the site of formation of amyloid fibrils in the brain. The identification of these cells as a place where ~-amyloid fibrils are made is as important as Glenner and Wong's [8, 9] findings concerning the sequence of vascular amyloid from AD brains. These studies led to the discovery of a novel protein, the amyloid precursor protein (APP), its gene and the chromosome on which the APP gene is located [11, 31, 34].We expect that the discovery of the cells making amyloid fibrils will lead to their isolation and to the identification of the genetic and/or biochemical defect(s) responsible for failure of these cells to properly make or process the APE with tragic consequences to the AD victim.

Acknowledgements. The authors wishto thank Maureen Stoddard Marlow for copy-editingthe manuscript, and Dr. Julia Currie for critical review of the text.

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Ultrastructural studies of the cells forming amyloid in the cortical vessel wall in Alzheimer's disease.

Ultrastructural studies of serial sections of the vessels with amyloid deposits in the brain cortex of patients with Alzheimer's disease showed that c...
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