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Proteoglycans, glycosaminoglycans, amyloid-enhancing factor, and amyloid deposition K. KISILEVSKY Vroiri tlrc Ueprrtimwt o/ Potlrology. Queeri’s Uriiversity. mid the Syl mid M(J//!/ Apps Kesenrcli Cciiter. Kirigstori Gerreral Hospital. Kirigstori. Oritario. Corircda

Common elements in amyloidosis Several common elements have now been identified in various amyloid deposits. These include the serum amyloid 1’ component (SAP) and the glycosaminoglycans (GAGs), both of which are found in all amyloids, and amyloid-enhancing factor (AEF).GAGs and AEP are considered below.

Glycosaminoglycans and amyloidosis GAGs arc linear polysaccharide chains composed of repeating disaccharide units. The disaccharide unit is usually composed of a uronic acid and a hexosamine. With the exception of hyaluronic acid, all GAGs are covalently linked to a protein backbone, and the entire molecule is called a proteoglycan. GAGs have been known to be present in amyloid deposits for many years. Interest in these components as they relate to amyloid deposition was reawakened when it was demonstrated that GAGs were deposited coincidentally with the murine amyloid A (AA) protein no matter how the experimental amyloidogenesis protocol was manipulated [ I ]. These observations initiated work that identified the GAGs as being heparan sulphate, and this work in turn led to the demonstration that the heparan sulphate was part of a large proteoglycan, the heparan sulphate proteoglycan (HSPG) of the basement membrane type. More recent work has suggested that perhaps several other GAGs may be associated with different types of amyloid. However, where the GAGs have been identified. heparan sulphate seems to be the common element. HSPG has now been demonstrated in at least five distinct forms of amyloid [21. These include AA or inflammatory-associated amyloid : AL- or immunoglobulin-associated amyloid: islet amyloid polypeptide associated with adult-onset diabetes : /I amyloid in Alzheimer’s disease : prion amyloids in Creutzfeldt-Jakob disease, scrapie, and Gerstmann-

Straussler-Scheinker syndrome: and transthyretin in familial amyloidotic polyneuropathy. In murine experimental models in which it is possible to examine the amyloid shortly after it has been deposited, the HSPG has been shown to be a n integral component of the amyloid fibril 131. In human deposits, the protein backbone of the GAG is apparently absent [4], a suggestion that this protein core may be removed proteolytically as the amyloid deposit ages. These results further suggest that the GAG moiety may be important in maintaining fibril structure, possibly through the highly negatively charged sulphate groups. The significance of the proteoglycan in amyloid fibril formation is only now being investigated. Very specific high-affinity interactions have been shown to occur between the HSPG and the various forms of the Alzheimer’s amyloid precursor proteins 151. This interaction, although apparently occurring primarily through proteinprotein binding, nevertheless can be inhibited by heparan and dextran sulphate but not by chondroitin and dermatan sulphate. This indicates a role for specific sulphated carbohydrate moieties. Preliminary evidence indicates that these high-affinity interactions also occur with two other amyloid precursors: serum amyloid A (SAA), the precursor to AA, and &,-microglobulin (P,-M), the precursor to dialysis-associated amyloid (Ancsin & Kisilevsky, unpublished results). Furthermore, heparan sulphate, as opposed to several other GAGs, influences SAA to undertake a marked increase in &pleated sheeting, which is the characteristic protein conformation of all amyloids 161. As mentioned above, HSPG found in amyloid deposits has been shown to be of the basement membrane type. Although the interaction of amyloidogenic precursors with HSPG or heparan sulphate is a specific focus of amyloid research, it has become

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apparent that this issue is probably part of a much larger metabolic or biologic problem that is occurring during amyloidogenesis. HSPG of the basement membrane type is not usually expressed in isolation. This protein is usually synthesized in conjunction with laminin, collagen-IV, and fibronectin. A fundamental disturbance in basement membrane metabolism during amyloidogenesis is suggested by these data. The interactive properties of amyloidogenic precursors with collagen-IV, laminin, and fibronectin are also now under study, and preliminary data indicate binding properties very similar to those with HSPG (Narindrasorasak, Ancsin & Kisilevsky, unpublished results). These interactions may reflect events during the nucleation stages of amyloidogenesis.

Amyloid-enhancing factor The ability to accelerate AA deposition with the use of extracts from amyloid-containing tissue was recognized approximately 10 years ago [71. When transferred to isogeneic recipients, immunologically competent spleen cells from amyloidotic animals produced amyloid deposition within 36 h, provided that the recipients were also exposed to an acute inflammatory stimulus [7]. Neither stimulus alone was effective in inducing amyloid. Sonicated spleen cells were just as effective as the intact cells. This finding pointed to a cellular component as the active agent rather than to an immunologic property that resided in the intact cell. Thus, AEF was defined by its biologic properties. With the use of standard AA induction protocols, it was demonstrated that AEF actively appeared in tissues some 24 to 48 h before actual amyloid deposition [7]. Thus, the transfer experiments described earlier simply removed the lag phase for the natural generation of AEF in such animals, and this change allowed amyloid deposition to commence as soon as adequate precursor quantities were available. Attempts to purify AEF have been only partially successful. Early work demonstrated that AEF was a large complex that would lose biological activity when digested with proteases or periodic acid [71-a suggestion that the active component contained both protein and carbohydrate. More recent work has suggested that the active component is relatively small (between 8 and 16 kDa). Purified AA protein,

SAP, and GAGS all lack activity, but small fragments of amyloid fibrils are effective [8]; thus, AEF may be a complex of several components that lose their activity when dissociated. An alternative is that small amyloid fibrils may be a nidus for further amyloid deposition. AEF activity has been extracted from various forms of amyloid, including AA, AL, transthyretin, and Alzheimer’s-diseased brains [9, 101. Whether AEF is a single entity, a nidus, or a general reaction on the part of specific cell types to several different components has yet to be established.

References 1 Snow All. Kisilevsky K. Temporal relationship between glycosaminoglycan accumulation and timyloid deposition during experimental amyloidosis : a histochemical study. Inib Invest 1985: 5 3 : 3 7 4 4 . 2 Kisilevsky R. Heparan sulfate proteoglycans in amyloidogenesis: an epiphenomenon, a unique factor. or the tip of ii more fundamental process? Intb lrrvest 1990: 6 3 : 589-91. 3 Snow All. Bramson R. Mar H. Wight TN, Kisilevsky K. A temporal and ultrastructural relationship between heparan sulfate proteoglycans and AA amyloid in experimental aniyloidosis. / Histocherti Cgtoclterti 1991 ; 3 9 : 132 1-30, 4 Nelson SK. Lyon M. Gallagher JT. Johnson LA. I’epys MB. Isolation and characterization of the integral glycosaminoglycan constituents of human amyloid A and monoclonal light-chain amyloid fibrils. Miocherti / 1991 : 2 7 5 : 67-73, 5 Narindrasorasak S. Lowery I). Gonzalc%DeWhitt P. I’oorman KA. Greenberg H. Kisilevsky R. High affinity interactions between the Alzheimer’s /j’-amyloid precursor proteins and the basement membrane form of heparan sulfate protcoglycan. / No1 Clierrt 1991: 2 6 6 : 12878-83. 6 McCubbin WD. Kay CM. Narindrasorasak S. Kisilevsky K. Circular-dichroism studies on two niurine serum amyloid A proteins. Hioclrerri / 1 9 8 8 ; 2 5 6 : 755-83. 7 Axelrad MA. Kisilevsky K. Willnier J. Chen SJ. Skinner M. Further characterization of amyloid-enhancing fktor. I d ) lrivest 1982: 4 7 : 139-46. 8 Niewold ThA. Hol PR. van Andel ACJ. Lutz ETG. Gruys 1:. Enhancement ofamyloid induction by amyloid libril fragments in hamster. Lab Itrvest 1987: 56: 544-9. 9 Varga J , Flinn MSM. Shirhama T. Rodgers OG. Cohen AS. The induction of accelerated murine amyloid with human splenic extract: probable role of amyloid enhancing factor. Virc:hows Arch H Cell Pntliol 1986: 51 : 177-85. 10 Ali-Khan %. Quirion R. Robitaille Y . Aliaadeh-Khisvi K. I>u T. Evidence for increased amyloid enhancing factor activity in Alzheimer brain extract. Actn Nettropnthol ( H e r l ) 1988 : 77 : 82-90.

Received 10 June 1992. accepted 23 June 1992 Corresporirletire: Robert A. Kyle, MU. Mayo Clinic, 2 0 0 First Street SW. Rochester. Minnesota 55905. USA.

Proteoglycans, glycosaminoglycans, amyloid-enhancing factor, and amyloid deposition.

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