Neuroscience Letters, 140 (1992) 137-140
137
© 1992 Elsevier Scientific Publishers Ireland Ltd. All rights reserved 0304-3940/92/$ 05.00 NSL 08696
Acute phase proteins but not activated microglial cells are present in parenchymal fl/A4 deposits in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type J.M. Rozemuller a'b, G.T.A.M. Bots c, R.A.C. R o o s d and P. Eikelenboom a Department of "Psychiatry and hNeuropathology, Free University of Amsterdam, Amsterdam (Netherlands) and Department of "Neuropathology and dNeurology, State University of Leyden, Leyden (Netherlands) (Received 19 December 1991; Revised version received 23 March 1992; Accepted 23 March 1992)
Key words: Hereditary cerebral hemorrhage with amyloidosis-Dutch type; Alzheimer's disease; fl/A4 amyloid; Acute phase protein; Microglial cell With immunohistochemical staining methods on cryostat sections we investigated the brains of three patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type, one of the cerebral fl/A4 amyloid diseases. Immunostaining for fl/A4 protein revealed numerous non-fibrillar fl/A4 depositions (amorphous or diffuse plaques) in the brain parenchyma in addition to extensive vascular amyloid deposition. All amorphous plaques contain complement proteins and cq-antichymotrypsin but activated microglial cells expressing major histocompatibility (MHC) class II antigens HLA-DR and leucocyte adhesion molecules belonging to the lymphocyte-function-associated antigen (LFA)-I family are virtually absent in cortical gray matter. Our findings are discussed from the view that a cascade of events including acute phase proteins and activated microglial cells are involved in classical amyloid plaque formation.
Hereditary cerebral hemorrhage with amyloidosisDutch type (HCHWA-D) is like Alzheimer's disease (AD), one of the cerebral fl/A4-amyloid diseases [9, 15, 25]. It is an autosomal dominant inherited disorder characterized by occurrence of cerebral haemorrhages in the 5th and 6th decade of life [26]. Recent findings show that HCHWA-D is caused by an abnormal variant of the fl/ A4 amyloid precursor protein (APP) [2, 11, 24]. In the brains of HCHWA-D patients an extensive amyloid deposition in leptomeningeal and cortical small and medium sized vessels is found. In addition to congophilic vessels a variable number of parenchymal fl/A4 deposits in nonfibrillar form, not associated with abnormal neurites (the so-called amorphous, diffuse or preamyloid plaques) are present. Classical plaques and neurofibrillary degeneration, however, are not observed [9, 12, 23, 25]. The question why plaque formation in HCHWA-D stops at an early stage before classical amyloid plaques develop can yet not be answered [9]. Advances in molecular analysis of cerebral amyloid deposition in AD have provided evidence for a pathogenic cascade mechanism including acute phase proteins and activated microglia in classical Correspondence: J.M. Rozemuller, Department of Neuropathology, Free University Hospital, Postbox 7057, 1007 MB Amsterdam, Netherlands.
amyloid plaque formation [6, 21]. Using immunohistochemical techniques, complement factors [7] ~l-antichymotrypsin (ACT) [1] and P-component [3] but no common serum proteins (such as albumin and fibrinogen) [18] have been found in classical and amorphous plaques [20] in AD. Reports concerning immunoglobulins in plaques are unequivocal [10, 20]. In the cortical gray matter of patients with AD increased numbers of small glial cells (referred to as microglial cells) expressing major histocompatibility complex class II antigens HLA-DR [14, 16, 20] and leucocyte adhesion molecules of the lymphocyte-function associated antigen (LFA)-I family [19] are found. These markers appear to be constitutively present on microglial cells in the normal white matter but are induced or upregulated on microglia in the grey matter in association with amyloid deposits in AD [13, 19]. Formalin fixation and paraffin embedding strongly compromise immunostaining for the fl/A4 associated molecules, such as complement proteins and ACT and the monocyte/macrophage markers expressed in activated microglial cells [16, 18, 20]. We report here that parenchymal fl/A4 depositions in amorphous plaques in the cerebral cortex of patients with HCHWA-D contain both complement proteins and ACT but do not show relationships with activated microglial cells. We have carried out an immunohistochemical study
138 !??
Fig. 1. Frozen section of parietal staining for A C T Fig. 2. Frozen section of parietal staining for C3d
cortex of a 42 year old H C H W A - D patient who died from cerebral hemorrhages, lmmunohistochemical double (brown) and fl/A4 (blue). All diffuse plaques are double stained for A C T and ,8/A4. Bar = 40/,tin, cortex of a 47 year old H C H W A - D patient who died from cerebral hemorrhages. Immunohistochemical double (brown) and fl/A4 (blue). All diffuse plaques are double stained for C3d and fl/A4. Bar = 20 y m .
on the cerebral cortex o f three H C H W A - D cases aged 42, 47 and 50 years. Brain tissue of two Alzheimer patients was used as positive control. Parietal tissue was frozen postmortem and cut on the cryostat (8 ~tm). Sec-
tions were mounted on poly-L-lysine coated glass slides, air-dried and immunostained overnight after 10 min acetone fixation. The antisera and monoclonals used in this study are listed in Table I. Sections were immunostained
TABLE I A N T I S E R A A N D M O N O C L O N A L S U S E D IN THIS S T U D Y Antibody (antigen)
Raised in
Source
fl/A4 antiserum
rabbit rabbit mouse rabbit mouse mouse mouse
Gift, C.L. Masters and K. Beyreuther" DAKOPATTS Gilt, C.E. Hack b DAKOPATTS Gift, C.E. Hack h Ortho-mune Becton & Dickinson
A C T polyclonal A C T monoclonal Complement C I q Complement C3d M H C class II (OKIa) LFA-1, s-chain (CDI lc) LeuM5
~'C.L. Masters, Department of Pathology, University of Melbourne, Australia. ~'C.E. Hack, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam, Netherlands.
139
for fl/A4 protein, ACT, complement proteins Clq and C3d, MHC class II glycoprotein HLA-DR and for leucocyte adhesion molecules belonging to the LFA-1 family as described before [4, 17, 19, 20]. Double immunostaining was performed by incubating overnight simultaneously with anti-fl/A4 rabbit polyclonal antibodies and anti-C3d or anti-ACT monoclonal antibodies, followed in the second step by an incubation with alkaline-phosphatase labelled goat-anti-rabbit (Tago) and biotinylated horse anti-mouse antibodies (Vector). In the third step sections were incubated with peroxidase labelled avidin-biotin complex (Vector elite kit). Peroxidase activity was visualized using the DAB method. Alkaline phosphatase was revealed using naphtol AS-MX phosphate as substrate and Fast blue BB as coupling agent. Secondary antisera and reagents were tested for lack of cross-reactivity and non-specific binding. The findings in HCHWA-D patients were as follows: (i) in addition to extensive vascular amyloid deposition immunostaining for fl/A4 protein shows numerous amorphous non-congophilic plaques in the brain parenchyma of all three studied cases. (ii) Immunostaining for C lq and C3d, and ACT show also numerous plaque-like depositions in brain parenchyma. Double immunostaining for fl/A4 protein and ACT and for A4 and complement factor C3d shows that fl/A4 deposits in brain parenchyma are always immunolabelled for ACT and C3d (Figs. 1 and 2). (iii) Microglial cells showing immunoreactivity for MHC class II antigens or leucocyte adhesion molecules belonging to the LFA-1 family are only observed sporadically in the gray matter. In earlier studies on formol fixed paraffin embedded tissue, it was found that the density of the parenchymal fl/A4 deposits in HCHWA-D is much lower than in AD [22, 23, 25]. Only a few of these amorphousfl/A4 deposits showed immunostaining for ACT [23]. We found in the present study on frozen tissue a density of 40-60 amorphous plaques/mm in all three HCHWA-D cases. Moreover all these amorphous plaques contain complement proteins and ACT. There is at present growing evidence that in AD in selected brain regions under certain conditions amorphous plaques become increasingly fibrillar and compacted leading to classical amyloid plaque formation [5, 8, 20, 21]. In HCHWA-D, in contrast to AD, no classical plaques and no increase of activated microglial cells in the cortical grey matter are found in patients with HCHWA-D. These observations suggest that in the cascade of events leading to classical amyloid plaque formation the presence of activated microglial cells and the modification of fl/A4 proteins into congophilic amyloid fibrils are probably related events. The present findings support the idea that in 'cerebral fl/A4 amyloid diseases' parenchymal fl/A4 depositions contain complement pro-
teins and ACT from an early stage but the role of activated microglial cells is determined to the formation of classical plaques. This study was supported by Grant 28-1945 of the Dutch Prevention Fund. Brain tissue was also obtained from the Netherlands Brain Bank, Amsterdam (Coordinator Dr. R. Ravid). 1 Abraham, C.R., Selkoe, D.J. and Potter, H., Immunohistochemical identification of the serine protease inhibitor alphal-antichymo+ trypsin inhibitor in the brain amyloid deposits of Alzheimer's disease, Cell, 52 (1988) 487-501. 2 Bakker, E., van Broeckhoven, C., Haan, J., Voorhoeve, E., van Hull, W., Levy, E., Lieberburg, I., Carman, M.D., van Ommen, G.J.B. and Roos, R.A.C., DNA diagnosis for hereditary cerebral hemorrhage with amyloidosis (Dutch type), Am. J. Human Genet., 49 (1991) 518-521. 3 Coria, F., Castano, E., Prelli, F., Larrondo-Lillo, M., Van Duinen, S., Shelanski, M.L. and Frangione, B., Isolation and characterization of amyloid P-component from Alzheimer's disease and other cerebral amyloidosis, Lab. Invest., 58 (1988)45~458. 4 Eikelenboom, P., Hack, C.E., Rozemuller, J.M. and Stam, F.C., Complement activation in amyloid plaques in Alzheimer's disease, Virchows Arch. B, 56 (1989) 259-262. 5 Eikelenboom, P., Rozemuller, J.M., Fraser, H., Berkenbosch, F., Kamphorst, W. and Stam, F.C., Neuroimmunologic mechanism in cerebral amyloid deposition in Alzheimer's disease. In T. Ishii, D. Allsop and D.J. Selkoe (Eds.), Frontiers of Alzheimer Research+ Elsevier, Amsterdam, 1991,259-271. 6 Eikelenboom, P., Rozemuller, J.M., Kraal, G., Stare, F.C., McBride, P.A., Bruce, M.E. and Fraser, H., Cerebral amyloid plaques in Alzheimer's disease but not in scrapie-affected mice are closely associated with a local inflammatory process, Virchows Arch. B., 60 (1991) 329-336. 7 Eikelenboom, P. and Stam, F.C., Immunoglobulins and complement factors in senile plaques, Acta Neuropathol., 57 (1982) 239242. 8 Giaccone, G., Tagliavini, F., Linoli, G., Bouras, C., Frigerio, L., Frangione, B. and Bugiani, O., Down patients: extracellular preamyloid deposits precede neuritic degeneration and senile plaques, Neurosci. Lett., 97 (1989) 232-238. 9 Haan, J., Hardy, J.A. and Roos, R.A.C., Hereditary cerebral hemorrhage with amyloidosis-Dutch type: its importance for Alzheimer's disease, Trends Neurosci., 14 (1991) 231-234. 10 Ishii, T. and Haga, S., Immuno-electron microscopic localization of immunoglobulins in amyloid fibrils of senile plaques, Acta Neuropathol., 36 (1976) 243-249. 11 Levy, E., Carman, M.D., Fernandez-Madrid, l.J., Power, M.D., Lieberburg, I., van Duinen, S.G., Bots, G.T.A.M., Luyendijk, W. and Frangione, B., Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type, Science, 248 (1990) 1124-1126. 12 Luyendijk, W., Bots, G.T.A.M., Vegter-van der Vlis, M., Went, L.N. and Frangione, B., Hereditary cerebral hemorrhage caused by cortical amyloid angiopathy, J. Neurol. Sci., 85 (1988) 267 280. 13 Mattiace, L.A., Davies, P., Yen, S.-H. and Dickson, D.W., Microglia in cerebellar plaques in Alzheimer's disease, Acta Neuropathol., 80 (1990) 439498. 14 McGeer, P.L., Itagaki, S., Tago, H. and McGeer, E.G., Reactive microglia in patients with senile dementia of Alzheimer type are
140
15
16
17
18
19
20
positive for histocompatibility glycoprotein HLA-DR, Neurosci. Lett., 79 (1987) 195 200. Prelli, F., Castafio, E.M., van Duinen, S.G., Bots, G.T.A.M., Luyendijk, W. and Frangione, B., Different processing of Alzheimer's fl-protein precursor in the vesselwall of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type, Biochem. Biophys. Res. Commun., 115 (1988) 1150 1155. Rogers, J., Luber-Narod, J., Styren, S.D. and Civin, W.H., Expression of immune system associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease, Neurobiol. Aging, 9 (1988) 339 349. Rozemuller, J.M., Abbink, J., Stam, F.C., Hack, C.E. and Eikelenboom, E, Distribution pattern and functional state of al-antichymotrypsin in plaques and vascular amyloid in Alzheimer's disease, Acta Neuropathol., 82 (1991) 200 207. Rozemuller, J.M., Eikelenboom, P., Kamphorst, W. and Stare, F.C., Lack of evidence for dysfunction of the blood brain barrier in Alzheimer's disease: an immunohistochemical study, Neurobiol. Aging, 9 (1988) 383 391. Rozemuller, J.M., Eikelenboom, P., Pals, S.T. and Stam, F.C., Microglial cells around amyloid plaques in Alzheimer's disease express leucocyte adhesion molecules of the LFA-I family, Neurosci. Lett., 101 (1989) 288 292. Rozemuller, J.M., Eikelenboom, E, Stam, F.C., Beyreuther, K. and
21 22
23
24
25
26
Masters, C.L., A4 protein in AIzheimer's disease: primary and secondary cellular events in extracellular amyloid deposition, J. Neuropathol. Exp. Ncurol., 48 (1989) 647-663. Selkoe, D., The molecular pathology of Alzheimer's disease, Neuron, 6 (1991) 487- 498. Tagliavini, F., Ghiso, J., Timmers, W.F., Giaccone, G., Bugiani, O. and Frangione, B., Coexistence of Alzheimer's amyloid precursor protein and amyloid protein in cerebral vessel walls, Lab. Invest., 62 (1990) 761 766. Timmers, W.F., Tagliavini, F., Haan, J. and Frangione, B., Parenchymal preamyloid and amyloid deposits in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type, Neurosci. Lett., 118 (1990) 223 226. van Broeckhoven, C., Haan, J., Bakker, E., Hardy, J.A., Hul, W.V., Vegter-van der Vlis, M. and Roos, R.A.C., Amyloid ,&protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch), Science, 248 (1990) 1120 1122. van Duinen, S.G., Castano, EM., Prelli, F., Bots, G.T.A.M., Luyendijk, W. and Frangione, B., Hereditary cerebral hemorrhage with amyloidosis in patients of the Dutch origin is related to Atzheimer disease, Proc. Natl. Acad. Sci. U.S.A., 84 (1987) 5991 5994. Wattendorff, A., Bots, G.T.A.M., Went, L.N. and Endtz, L.J., Familial cerebral amyloid angiopathy presenting as recurrent cerebral haemorrhage, J. Neurol. Sci., 55 (1982) 121 135.
137
© 1992 Elsevier Scientific Publishers Ireland Ltd. All rights reserved 0304-3940/92/$ 05.00 NSL 08696
Acute phase proteins but not activated microglial cells are present in parenchymal fl/A4 deposits in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type J.M. Rozemuller a'b, G.T.A.M. Bots c, R.A.C. R o o s d and P. Eikelenboom a Department of "Psychiatry and hNeuropathology, Free University of Amsterdam, Amsterdam (Netherlands) and Department of "Neuropathology and dNeurology, State University of Leyden, Leyden (Netherlands) (Received 19 December 1991; Revised version received 23 March 1992; Accepted 23 March 1992)
Key words: Hereditary cerebral hemorrhage with amyloidosis-Dutch type; Alzheimer's disease; fl/A4 amyloid; Acute phase protein; Microglial cell With immunohistochemical staining methods on cryostat sections we investigated the brains of three patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type, one of the cerebral fl/A4 amyloid diseases. Immunostaining for fl/A4 protein revealed numerous non-fibrillar fl/A4 depositions (amorphous or diffuse plaques) in the brain parenchyma in addition to extensive vascular amyloid deposition. All amorphous plaques contain complement proteins and cq-antichymotrypsin but activated microglial cells expressing major histocompatibility (MHC) class II antigens HLA-DR and leucocyte adhesion molecules belonging to the lymphocyte-function-associated antigen (LFA)-I family are virtually absent in cortical gray matter. Our findings are discussed from the view that a cascade of events including acute phase proteins and activated microglial cells are involved in classical amyloid plaque formation.
Hereditary cerebral hemorrhage with amyloidosisDutch type (HCHWA-D) is like Alzheimer's disease (AD), one of the cerebral fl/A4-amyloid diseases [9, 15, 25]. It is an autosomal dominant inherited disorder characterized by occurrence of cerebral haemorrhages in the 5th and 6th decade of life [26]. Recent findings show that HCHWA-D is caused by an abnormal variant of the fl/ A4 amyloid precursor protein (APP) [2, 11, 24]. In the brains of HCHWA-D patients an extensive amyloid deposition in leptomeningeal and cortical small and medium sized vessels is found. In addition to congophilic vessels a variable number of parenchymal fl/A4 deposits in nonfibrillar form, not associated with abnormal neurites (the so-called amorphous, diffuse or preamyloid plaques) are present. Classical plaques and neurofibrillary degeneration, however, are not observed [9, 12, 23, 25]. The question why plaque formation in HCHWA-D stops at an early stage before classical amyloid plaques develop can yet not be answered [9]. Advances in molecular analysis of cerebral amyloid deposition in AD have provided evidence for a pathogenic cascade mechanism including acute phase proteins and activated microglia in classical Correspondence: J.M. Rozemuller, Department of Neuropathology, Free University Hospital, Postbox 7057, 1007 MB Amsterdam, Netherlands.
amyloid plaque formation [6, 21]. Using immunohistochemical techniques, complement factors [7] ~l-antichymotrypsin (ACT) [1] and P-component [3] but no common serum proteins (such as albumin and fibrinogen) [18] have been found in classical and amorphous plaques [20] in AD. Reports concerning immunoglobulins in plaques are unequivocal [10, 20]. In the cortical gray matter of patients with AD increased numbers of small glial cells (referred to as microglial cells) expressing major histocompatibility complex class II antigens HLA-DR [14, 16, 20] and leucocyte adhesion molecules of the lymphocyte-function associated antigen (LFA)-I family [19] are found. These markers appear to be constitutively present on microglial cells in the normal white matter but are induced or upregulated on microglia in the grey matter in association with amyloid deposits in AD [13, 19]. Formalin fixation and paraffin embedding strongly compromise immunostaining for the fl/A4 associated molecules, such as complement proteins and ACT and the monocyte/macrophage markers expressed in activated microglial cells [16, 18, 20]. We report here that parenchymal fl/A4 depositions in amorphous plaques in the cerebral cortex of patients with HCHWA-D contain both complement proteins and ACT but do not show relationships with activated microglial cells. We have carried out an immunohistochemical study
138 !??
Fig. 1. Frozen section of parietal staining for A C T Fig. 2. Frozen section of parietal staining for C3d
cortex of a 42 year old H C H W A - D patient who died from cerebral hemorrhages, lmmunohistochemical double (brown) and fl/A4 (blue). All diffuse plaques are double stained for A C T and ,8/A4. Bar = 40/,tin, cortex of a 47 year old H C H W A - D patient who died from cerebral hemorrhages. Immunohistochemical double (brown) and fl/A4 (blue). All diffuse plaques are double stained for C3d and fl/A4. Bar = 20 y m .
on the cerebral cortex o f three H C H W A - D cases aged 42, 47 and 50 years. Brain tissue of two Alzheimer patients was used as positive control. Parietal tissue was frozen postmortem and cut on the cryostat (8 ~tm). Sec-
tions were mounted on poly-L-lysine coated glass slides, air-dried and immunostained overnight after 10 min acetone fixation. The antisera and monoclonals used in this study are listed in Table I. Sections were immunostained
TABLE I A N T I S E R A A N D M O N O C L O N A L S U S E D IN THIS S T U D Y Antibody (antigen)
Raised in
Source
fl/A4 antiserum
rabbit rabbit mouse rabbit mouse mouse mouse
Gift, C.L. Masters and K. Beyreuther" DAKOPATTS Gilt, C.E. Hack b DAKOPATTS Gift, C.E. Hack h Ortho-mune Becton & Dickinson
A C T polyclonal A C T monoclonal Complement C I q Complement C3d M H C class II (OKIa) LFA-1, s-chain (CDI lc) LeuM5
~'C.L. Masters, Department of Pathology, University of Melbourne, Australia. ~'C.E. Hack, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam, Netherlands.
139
for fl/A4 protein, ACT, complement proteins Clq and C3d, MHC class II glycoprotein HLA-DR and for leucocyte adhesion molecules belonging to the LFA-1 family as described before [4, 17, 19, 20]. Double immunostaining was performed by incubating overnight simultaneously with anti-fl/A4 rabbit polyclonal antibodies and anti-C3d or anti-ACT monoclonal antibodies, followed in the second step by an incubation with alkaline-phosphatase labelled goat-anti-rabbit (Tago) and biotinylated horse anti-mouse antibodies (Vector). In the third step sections were incubated with peroxidase labelled avidin-biotin complex (Vector elite kit). Peroxidase activity was visualized using the DAB method. Alkaline phosphatase was revealed using naphtol AS-MX phosphate as substrate and Fast blue BB as coupling agent. Secondary antisera and reagents were tested for lack of cross-reactivity and non-specific binding. The findings in HCHWA-D patients were as follows: (i) in addition to extensive vascular amyloid deposition immunostaining for fl/A4 protein shows numerous amorphous non-congophilic plaques in the brain parenchyma of all three studied cases. (ii) Immunostaining for C lq and C3d, and ACT show also numerous plaque-like depositions in brain parenchyma. Double immunostaining for fl/A4 protein and ACT and for A4 and complement factor C3d shows that fl/A4 deposits in brain parenchyma are always immunolabelled for ACT and C3d (Figs. 1 and 2). (iii) Microglial cells showing immunoreactivity for MHC class II antigens or leucocyte adhesion molecules belonging to the LFA-1 family are only observed sporadically in the gray matter. In earlier studies on formol fixed paraffin embedded tissue, it was found that the density of the parenchymal fl/A4 deposits in HCHWA-D is much lower than in AD [22, 23, 25]. Only a few of these amorphousfl/A4 deposits showed immunostaining for ACT [23]. We found in the present study on frozen tissue a density of 40-60 amorphous plaques/mm in all three HCHWA-D cases. Moreover all these amorphous plaques contain complement proteins and ACT. There is at present growing evidence that in AD in selected brain regions under certain conditions amorphous plaques become increasingly fibrillar and compacted leading to classical amyloid plaque formation [5, 8, 20, 21]. In HCHWA-D, in contrast to AD, no classical plaques and no increase of activated microglial cells in the cortical grey matter are found in patients with HCHWA-D. These observations suggest that in the cascade of events leading to classical amyloid plaque formation the presence of activated microglial cells and the modification of fl/A4 proteins into congophilic amyloid fibrils are probably related events. The present findings support the idea that in 'cerebral fl/A4 amyloid diseases' parenchymal fl/A4 depositions contain complement pro-
teins and ACT from an early stage but the role of activated microglial cells is determined to the formation of classical plaques. This study was supported by Grant 28-1945 of the Dutch Prevention Fund. Brain tissue was also obtained from the Netherlands Brain Bank, Amsterdam (Coordinator Dr. R. Ravid). 1 Abraham, C.R., Selkoe, D.J. and Potter, H., Immunohistochemical identification of the serine protease inhibitor alphal-antichymo+ trypsin inhibitor in the brain amyloid deposits of Alzheimer's disease, Cell, 52 (1988) 487-501. 2 Bakker, E., van Broeckhoven, C., Haan, J., Voorhoeve, E., van Hull, W., Levy, E., Lieberburg, I., Carman, M.D., van Ommen, G.J.B. and Roos, R.A.C., DNA diagnosis for hereditary cerebral hemorrhage with amyloidosis (Dutch type), Am. J. Human Genet., 49 (1991) 518-521. 3 Coria, F., Castano, E., Prelli, F., Larrondo-Lillo, M., Van Duinen, S., Shelanski, M.L. and Frangione, B., Isolation and characterization of amyloid P-component from Alzheimer's disease and other cerebral amyloidosis, Lab. Invest., 58 (1988)45~458. 4 Eikelenboom, P., Hack, C.E., Rozemuller, J.M. and Stam, F.C., Complement activation in amyloid plaques in Alzheimer's disease, Virchows Arch. B, 56 (1989) 259-262. 5 Eikelenboom, P., Rozemuller, J.M., Fraser, H., Berkenbosch, F., Kamphorst, W. and Stam, F.C., Neuroimmunologic mechanism in cerebral amyloid deposition in Alzheimer's disease. In T. Ishii, D. Allsop and D.J. Selkoe (Eds.), Frontiers of Alzheimer Research+ Elsevier, Amsterdam, 1991,259-271. 6 Eikelenboom, P., Rozemuller, J.M., Kraal, G., Stare, F.C., McBride, P.A., Bruce, M.E. and Fraser, H., Cerebral amyloid plaques in Alzheimer's disease but not in scrapie-affected mice are closely associated with a local inflammatory process, Virchows Arch. B., 60 (1991) 329-336. 7 Eikelenboom, P. and Stam, F.C., Immunoglobulins and complement factors in senile plaques, Acta Neuropathol., 57 (1982) 239242. 8 Giaccone, G., Tagliavini, F., Linoli, G., Bouras, C., Frigerio, L., Frangione, B. and Bugiani, O., Down patients: extracellular preamyloid deposits precede neuritic degeneration and senile plaques, Neurosci. Lett., 97 (1989) 232-238. 9 Haan, J., Hardy, J.A. and Roos, R.A.C., Hereditary cerebral hemorrhage with amyloidosis-Dutch type: its importance for Alzheimer's disease, Trends Neurosci., 14 (1991) 231-234. 10 Ishii, T. and Haga, S., Immuno-electron microscopic localization of immunoglobulins in amyloid fibrils of senile plaques, Acta Neuropathol., 36 (1976) 243-249. 11 Levy, E., Carman, M.D., Fernandez-Madrid, l.J., Power, M.D., Lieberburg, I., van Duinen, S.G., Bots, G.T.A.M., Luyendijk, W. and Frangione, B., Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type, Science, 248 (1990) 1124-1126. 12 Luyendijk, W., Bots, G.T.A.M., Vegter-van der Vlis, M., Went, L.N. and Frangione, B., Hereditary cerebral hemorrhage caused by cortical amyloid angiopathy, J. Neurol. Sci., 85 (1988) 267 280. 13 Mattiace, L.A., Davies, P., Yen, S.-H. and Dickson, D.W., Microglia in cerebellar plaques in Alzheimer's disease, Acta Neuropathol., 80 (1990) 439498. 14 McGeer, P.L., Itagaki, S., Tago, H. and McGeer, E.G., Reactive microglia in patients with senile dementia of Alzheimer type are
140
15
16
17
18
19
20
positive for histocompatibility glycoprotein HLA-DR, Neurosci. Lett., 79 (1987) 195 200. Prelli, F., Castafio, E.M., van Duinen, S.G., Bots, G.T.A.M., Luyendijk, W. and Frangione, B., Different processing of Alzheimer's fl-protein precursor in the vesselwall of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type, Biochem. Biophys. Res. Commun., 115 (1988) 1150 1155. Rogers, J., Luber-Narod, J., Styren, S.D. and Civin, W.H., Expression of immune system associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease, Neurobiol. Aging, 9 (1988) 339 349. Rozemuller, J.M., Abbink, J., Stam, F.C., Hack, C.E. and Eikelenboom, E, Distribution pattern and functional state of al-antichymotrypsin in plaques and vascular amyloid in Alzheimer's disease, Acta Neuropathol., 82 (1991) 200 207. Rozemuller, J.M., Eikelenboom, P., Kamphorst, W. and Stare, F.C., Lack of evidence for dysfunction of the blood brain barrier in Alzheimer's disease: an immunohistochemical study, Neurobiol. Aging, 9 (1988) 383 391. Rozemuller, J.M., Eikelenboom, P., Pals, S.T. and Stam, F.C., Microglial cells around amyloid plaques in Alzheimer's disease express leucocyte adhesion molecules of the LFA-I family, Neurosci. Lett., 101 (1989) 288 292. Rozemuller, J.M., Eikelenboom, E, Stam, F.C., Beyreuther, K. and
21 22
23
24
25
26
Masters, C.L., A4 protein in AIzheimer's disease: primary and secondary cellular events in extracellular amyloid deposition, J. Neuropathol. Exp. Ncurol., 48 (1989) 647-663. Selkoe, D., The molecular pathology of Alzheimer's disease, Neuron, 6 (1991) 487- 498. Tagliavini, F., Ghiso, J., Timmers, W.F., Giaccone, G., Bugiani, O. and Frangione, B., Coexistence of Alzheimer's amyloid precursor protein and amyloid protein in cerebral vessel walls, Lab. Invest., 62 (1990) 761 766. Timmers, W.F., Tagliavini, F., Haan, J. and Frangione, B., Parenchymal preamyloid and amyloid deposits in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type, Neurosci. Lett., 118 (1990) 223 226. van Broeckhoven, C., Haan, J., Bakker, E., Hardy, J.A., Hul, W.V., Vegter-van der Vlis, M. and Roos, R.A.C., Amyloid ,&protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch), Science, 248 (1990) 1120 1122. van Duinen, S.G., Castano, EM., Prelli, F., Bots, G.T.A.M., Luyendijk, W. and Frangione, B., Hereditary cerebral hemorrhage with amyloidosis in patients of the Dutch origin is related to Atzheimer disease, Proc. Natl. Acad. Sci. U.S.A., 84 (1987) 5991 5994. Wattendorff, A., Bots, G.T.A.M., Went, L.N. and Endtz, L.J., Familial cerebral amyloid angiopathy presenting as recurrent cerebral haemorrhage, J. Neurol. Sci., 55 (1982) 121 135.
