Bram Research, 541 (1991) 347-349 Elsevier
347
BRES 24536
Tropomyosin distinguishes Lewy bodies of Parkinson disease from other neurofibrillary pathology Pamela G Galloway 1 and George Perry 2 ;Department of Pathology, Children's Hospital Medical Center of Akron, Akron, OH 44308 (U S A ) and 21nstttute of Pathology, Case Western Reserve University, Cleveland, OH 44106 (U S A)
(Accepted 6 November 1990) Key words Tau, Neurofibrlllary tangle, Paired helical filament, Straight filament, Cytoskeleton
Research into the cellular changes in the degenerative diseases of the central nervous system has focused on the alterations in the constituent proteins of the neuronal cytoskeleton Although both mierotubule and neurofilament proteins have been implicated in the formation of neurofibnllary pathology m AIzhelmer, Pick, diffuse Lewy body and Parklnson diseases and progressive supranuclear palsy (PSP), until recently there has been httle consideration of whether other cytoskeletal systems are revolved With the finding that epltopes of the mlcrofilament associated protein tropomyosln are present in the neuroflbrillary pathology of Aizhelmer disease, we decided to investigate the presence of this protein in these related diseases To address whether the inclusion bodies of other degenerative diseases share this property, sections of brain were immunostained with antibodies to smooth and skeletal muscle tropomyosln Although neurofibnllary tangles in PSP, Pick bodies and some diffuse Lewy bodies stained, Lewy bodies of idiopathic Parkmson disease did not This property further distinguishes the Lewy body of Parkmson disease from other neurofibnllary pathologies The characteristic Intraneuronal inclusion bodies of the degenerative central nervous system diseases, Alzheimer and progressive supranuclear palsy, Pick, Parkinson and diffuse Lewy body disease have been extenswely investigated both by electron microscopy 2'15'34 and lmmunocytochemistryX,6,9-13 16-18 22-26,28-32 35-38 Both the sharmg of epttopes with, and the structural similarity of the filamentous inclusions to the normal neuronal cytoskeleton suggest that the inclusion body filaments may in some way be derived from the cytoskeleton This may be either from self-assembly of proteins into filaments or a degeneration or transformation of the pre-existing cytoskeleton We have investigated whether the neurofibrdlary pathology of progressive supranuclear palsy (PSP), Pick bodies of Pick disease and Lewy bodies of idiopathic Parkinson disease and diffuse Lewy body disease share epitopes with the mlcrofilament-associated protein tropomyosm 27 We found that Pick bodies, PSP tangles and some Lewy bodies m the cortex share epitopes with tropomyosm, yet Lewy bodies in idiopathic Parkinson disease do not, further distinguishing the latter mclusion Bralnstem sections were taken from two confirmed cases of progressive supranuclear palsy (range 52-65 yr) Cerebral cortex from two cases of Ptck disease (range 54-67 yr), and one case of diffuse Lewy body disease (age 70 yr) and secttons of locus coeruleus and/or substantm nlgra were obtained from nine patients with tdlopathic Parklnson disease (range 54-89 yr) Tissue was fixed
either in Bouln's fixative or 10% formalin with phosphate buffer, p H 7 0, before dehydration and embedding in paraffin Sections were cut at 6 micrometers The following antibodies were used rabbit antlsera raised to (a) chicken gizzard tropomyosln (gifts of Dr R Goldman and F Matsumura) affinity purified to tropomyosln and (b) skeletal muscle tropomyosin, and characterized as previously described 3'8 Sections were lmmunostalned with the antibodies by employing the peroxldase antlperoxldase procedure 33 with 3,3"-dlamlnobenzldlne as cosubstrate Photographs were taken on a Zelss Axlophoto equipped with Nomarskt planapochromatlc optics The neurofibrlllary pathology of progressive supranuclear palsy (Fig 1A), and Pick (Fig 1B) and diffuse Lewy body (Fig 1C) disease were stained with both antibodies to tropomyosin Lewy bodies of tchopathlc Parklnson disease remained unstained (Fig 1D) In control sections in which the primary antibody was replaced by normal goat serum, all the mcluslons remained unstained Our results show that a protein other than r, MAP2, ubtquitln or neurofilaments, and antigenically related to tropomyosin, ts present m the filamentous inclusions of progressive supranuclear palsy and Pick and diffuse Lewy body diseases Finding tropomyosin in all these inclusions implicates mlcrofilament involvement in neuroflbnllary pathologies The relatedness of the Hirano body, another impor-
Correspondence P G Galloway, Department of Pathology, 281 Locust Street, Akron, OH 44308, U S A
0006-8993/91/$03 50 (~) 1991 Elsevier Soence Pubhshers B V (Biomedical Division)
348 ~b
~r
Fig 1 Sections lmmunostamed with the affinity purified tropomyosm antibody A neurofibnllary tangles sn the bramstem of progressive supranuclear palsy B Pick bodies m Pick disease are tmmunostalned C diffuse Lewy bodies m the cortex are lmmunostamed D Lewy body in substantm mgra from idiopathic Parkmson disease is unstained (peroxldase-anti-peroxtdase, Nomarsk 0 Scale bar = 25/~m
tant intraneuronal inclusion seen in Alzhelmer patients, to tropomyosln has been shown both lmmunocytochemically3 and by 3-dimensional electron microscopy 19 The presence of tropomyosln, an actin associated protein 27, in Hlrano bodies had been suggested by the previous finding of actln I° In contrast, the presence of actln has not been observed in the neurofibrillary pathology of any disease 3 The exact pathogenetlc mechanism(s) involved in the pathogenesls of neurofibrlllary pathology have not been elucidated, despite lncreasmg knowledge as to protelnaceous composmon However, the similarity of the ultrastructural appearance of the Hlrano body and that of tropomyosln crystalhne arrays 19 suggests that the formation of these arrays may be part of a generalized irreversible crystallization of cytoskeletal proteins in Alzhelmer d~sease 2° Indeed, recent data, comparing the neurofllamentous network isolated from the giant axon of the squid (Lohgo pealel L ), compared with frontal lobe biopsies of Alzhelmer patients 21, suggest that the irreversible formation of para-crystalhne multi-protein assemblies by way of phase transmons may be a widespread mechanism m the pathogenesls of cytoskeletal alterations m Alzhelmer disease The apparent absence of tropomyosln from the Lewy
body of idiopathic Parklnson disease is lntngumg from the point of view of its apparent relatedness to the other filamentous mcluslons To date, Lewy bodies of idiopathic Parklnson disease have been shown to share ublqultm, MAP2 and neurofllament epltopes 7, as common properties with the other filamentous inclusions In contrast, Lewy bodies do not have r epltopes 7 Structurally, Lewy bodies consist of a dense central core with an array of 7-20 nm straight filaments 2 These filaments are distinct from paired helical filaments 15 of Alzhelmer disease and 15 nm straight filaments of Alzhelmer26 and Pick diseases z4 and PSP 34 The current findings further suggest that the Lewy body differs significantly from other neurofibrdlary pathologies Indeed both the cortical and subcortlcal Lewy bodies m diffuse Lewy body disease contain r 5 suggesting that idiopathic Parklnson disease may have a distract pathophyslology from those patients in which cortical structures are revolved, such as patients who have either diffuse Lewy body disease or combined Parkmson disease and Alzhelmer disease The authors thank Terl Hnat, Magdalena Mllares and Peggy Rtchey for assistance, and Mrs Mary Kay King for help preparing the manuscript
349
1 Anderton, B H , Bremberg, D , Dowries, M J . Green, P J , Tomhnson, B E , Ulrich, J , Wood, J M and Kahn, J , Nature, 298 (1982) 84-86 2 Forno, L S and NOrvllle, R L , Ultrastructure of Lewy bodies m the stellate ganghon, Acta Neuropathol, 34 (1976) 183-197 3 Galloway, P , Perry, G and Gambettl, O , Hlrano body fdaments contain actm and actln-assoclated proteins, J Neuropathol Exp Neurol, 46 (1987) 185-199 4 Galloway, P , Perry, G , Kosik, K and Gambettl, P, Hlrano bodies contain tan protein, Brain Research, 403 (1987) 337-340 5 Galloway, P G , Bergeron, C and Perry, G , The presence of tau distinguishes Lewy bodies of .dlopathlc Parkmson disease from those of diffuse Lewy body disease, Neurosct Left, 100 (1989) 6-10 6 Galloway, P G , AnUgemc charactensUcs of neurofibnllary tangles in progressive supranuclear palsy, Neurosct Lett, 91 (1988) 148-153 7 Galloway, P G , Grundke-Iqbal, I , Iqbal, K and Perry, G , Lewy bodies contain epltopes both shared and distract from Alzhelmer neurofibrillary tangles, J Neuropathol Exp Neurol , 47 (1988) 171-181 8 Galloway, P G , Muivlhfll, P , Siedlak, S , M1jares, M , Kawai, M , Padget, H , Klm, R and Perry, G , Immunochermcal demonstration of tropomyosln in the neurofibnllary pathology of Alzhelmer chsease, A m J Pathol, m press 9 Gambettl, P , Velasco, M E , Dahl, D , Blgnaml, A , Roessmann, U and Slndley, S D , Alzhelmer neurofibnllary tangles an immunohlstocfiemlcal study In L AmaduccI, A N Davidson and P Antuono (Eds), Aging of the Bratn and Dementta, New York, Raven Press, Vol 13, 1980, pp 55-63 10 Goldman, J E , The association of actln with Hirano bodies, J Neuropathol Exp Neurol, 42 (1983) 146-152 11 Grundke-Iqbal, I , Johnson, A B , Wlsmewski, H M , Terry, R D and Iqbal, K , Evidence that Alzhelmer's neurofibnilary tangles originate from neurotubules, Lancet, 1 (1979) 578-580 12 Grundke-Iqbal, I , Iqbal, K , Quinlan, M , Tung, Y C , Zaidl, M S and WlSnleWSkl, H M , M.crotubule-assoclated protein tau, a component of Alzhelmer paired hehcal filaments, J B~ol Chem, 261 (1986) 6084-6089 13 Grundke-Iqbal, I , Iqbal, K , Tung, Y C , Quinlan, M , Wlsniewskl. H M and Binder, L I , Abnormal phosphorylaUon of the mlcrotubule-assoc~ated protein (tan) in Alzhelmer cytoskeletal pathology, Proc Nail Acad Sct U S A , 83 (1986) 4913-4917 14 Khachutunan, Z S , Diagnos~s of Aizheimer's disease, Arch Neurol, 42 (1985) 1097-1105 15 I(add, M , Paired helical filaments m electron microscopy of AIzhelmer disease, Nature, 197 (1963) 192-193 16 Kos~k, K S , Duff),, L K , Dowhng, M M , Abraham. C , McCiuskey, A and Selkoe, D J , Mlcrotubule-assooated proteln 2 Monoclonal antibodies demonstrate the selecUve incorporation of certain epitopes into Alzhelmer neuroflbnllary tangles, Proc Natl Acad Sct U S A , 81 (1984) 7941-7945 17 Ks~ezak-Redmg, H , Dickson, D W, Davies, P and Yen, S H , Recogmt~on of tau epltopes by anti-neurofilament antibodies that brad to Alzhe~mer neurofibnllary tangles, Proc Natl Acad Sc~ U S A , 84 (1987) 3410-3414 18 Ksiezak-Redmg, H and Yen, S H , Two monoclonal antibodies recogmze Alzheimer's neuroflbnllary tangles, neurofilament, and m~crotubule-assooated protein, J Neurochem, 48 (1987) 455-462 19 Metuzals, J , Montpetlt, V, Clapln, D F and Nelson, R F , Filamentous arrays reminiscent of tropomyosln crystals in H~rano bodies of Alzhelmer disease (Abstract) In G W Bailey ( E d ) , Proceedings of the 41st Annual Meeang of the Electron Mtcroscopy Society of American, August 8-12, 1983, Phoenix, Arizona, San Francisco Press, San Fransisco, 1983, pp 532-533 20 Metuzals, J , Montpetit, V and Clapln, D F , Organization of the neurofilamentous network, Cell Tzssue Res, 214 (1981) 455-482
21 Metuzals, J , Pant. H , Gainer, H , Eagles, P A M , White. N S and Houghton, S , In vitro polymorphlsms and phase translUons of the neurofilamentous network isolated from the giant axon of the squid (Logllo peale~ L ), Cell T~ssue Res, 252 (1988) 249-262 22 Miller, C C , Brion, J P , Calvert, R , Chin, T K , Eagles, P A M , Downes, M J , Flament-Durant, J , Haugh, M , Kahn, J , Probst, A , Ulrich, J and Anderton, B H , AIzhelmer's paired helical filaments share epltopes with neurofilament side arms, EMBO J , 5 (1986) 269-276 23 Mulvihlll, P and Perry, G , Immunoafflmty demonstraUon that paired hehcal filaments of Alzhelmer disease share epltopes with both neurofilaments, MAP2 and tau, Brain Research, 420 (1989) 233-242 24 Mufioz-Garcfa, D and Ludwm, S K , Classical and generahzed variants of Pick's disease a chmcopathologlcal, ultrastructural, and immunocytochemlcal comparative study, Ann Neurol, 16 (1984) 467-480 25 Nukma, N , Koslk, K S and Selkoe, D J , Recogmtlon of Alzhelmer paired helical filaments by monoclonal neurofilament antibodies is due to cross-reaction with tan protein, Proc Natl Acad Sci U S A , 84 (1987) 3415-3419 26 Onorato, M , Mulvlhdl, P , Connolly, J , Galloway, P , Whitehouse, P J and Perry, G , Alteration of neuntlc cytoarchltecture In Alzheimer disease In K Iqbal, H M Wlsmewskl, and B Winblad (Eds), Alzhelmer's d~sease and Related Dtsorders, Alan R LISS, New York, 1989, pp 781-789 27 Payne, M R and RudnIck, S E , Tropomyosm structure and funcUonal diversity, Cell Muscle Mouhty, 6 (1985) 141-184 28 Perry, G , Rlzzuto, N , Autfllo-Gambetu, L and Gambettl, P , Paired hehcal filaments from Alzhelmer disease paUents contain cytoskeletal components, Proc Natl Acad Scl U S A , 81 (1985) 3916-3920 29 Perry, G , Friedman, R , Kang, D H , Manetto, V and Autfllo-Gambettl, P , Antibodies to the neuronal cytoskeleton are elicited by Alzhelmer paired hehcal filament fractions, Brain Research, 420 (1987) 233-242 30 Perry, G , Manetto, V , Onorato, M , We.ss, M , Galloway, P, Tabaton, M , Mulvlhlll, P , AuUho-Gambettl, L and Gambetu, P , Alterations of the neurofilament-mlcrotubule network m Alzhelmer and other neurodegeneraUve &sorders In G Perry (Ed), Alteraaons tn the Neuronal Cytoskeleton m Alzhamer Dtsease, Plenum Press, New York, 1987, pp 137-149 31 Perry, G , Stewart, D , Friedman, R , Manetto, V , AutlhoGambettl, L and Gambetti, P , Filaments of Pick's bodies contain altered cytoskeletal elements, A m J Pathol, 127 (1987) 559-568 32 Selkoe, D J , Biochemistry of altered brain proteins m Alzhelmer's disease, Annu Rev Neuroscl, 12 (1989) 463-490 33 Sternberger, L A , Immunocytochemtstry, 3rd e d n , 1986, New York, Wiley Press 34 Tellez-Nagel, I and Wlsmewskl, H M , Ultrastructure of neurofibnllary tangles in Stelle-Rlchardson-Olszewskl syndrome, Arch Neurol, 29 (1973) 324-327 35 Wlschlk, C M , Novak, M , Edwards. P C , Klug, A , Tlchelaar, W and Crowther, R A , Structural characterization of the core of the paired hehcal filament of Alzhelmer disease, Proc Nail Acad Sct U S A , 85 (1988) 295-299 36 Yen, S H , Gaskm, F and Terry, R D , Immunocytochemical studies of neurofibnllary tangles, A m J Pathol, 104 (1981) 77-89 37 Yen, S H , Horoupian, D S and Terry, R D , Immunocytochemlcal companson of neurofibnllary tangles in senile dementia of Alzhelmer type, progressive supranuclear palsy and postencephahtic parkmsomsm, Ann Neurol, 13 (1983) 172-175 38 Yen, S H , DIckson, D W , Crowe, A , Butler, M and Sheianskl, M L , AIzhelmer's neurofibnllary tangles contain unique epitopes and epitopes common w~th the heat-stable microtubuleassociated proteins, tau and MAP2, A m J Pathol, 126 (1987) 81-91
347
BRES 24536
Tropomyosin distinguishes Lewy bodies of Parkinson disease from other neurofibrillary pathology Pamela G Galloway 1 and George Perry 2 ;Department of Pathology, Children's Hospital Medical Center of Akron, Akron, OH 44308 (U S A ) and 21nstttute of Pathology, Case Western Reserve University, Cleveland, OH 44106 (U S A)
(Accepted 6 November 1990) Key words Tau, Neurofibrlllary tangle, Paired helical filament, Straight filament, Cytoskeleton
Research into the cellular changes in the degenerative diseases of the central nervous system has focused on the alterations in the constituent proteins of the neuronal cytoskeleton Although both mierotubule and neurofilament proteins have been implicated in the formation of neurofibnllary pathology m AIzhelmer, Pick, diffuse Lewy body and Parklnson diseases and progressive supranuclear palsy (PSP), until recently there has been httle consideration of whether other cytoskeletal systems are revolved With the finding that epltopes of the mlcrofilament associated protein tropomyosln are present in the neuroflbrillary pathology of Aizhelmer disease, we decided to investigate the presence of this protein in these related diseases To address whether the inclusion bodies of other degenerative diseases share this property, sections of brain were immunostained with antibodies to smooth and skeletal muscle tropomyosln Although neurofibnllary tangles in PSP, Pick bodies and some diffuse Lewy bodies stained, Lewy bodies of idiopathic Parkmson disease did not This property further distinguishes the Lewy body of Parkmson disease from other neurofibnllary pathologies The characteristic Intraneuronal inclusion bodies of the degenerative central nervous system diseases, Alzheimer and progressive supranuclear palsy, Pick, Parkinson and diffuse Lewy body disease have been extenswely investigated both by electron microscopy 2'15'34 and lmmunocytochemistryX,6,9-13 16-18 22-26,28-32 35-38 Both the sharmg of epttopes with, and the structural similarity of the filamentous inclusions to the normal neuronal cytoskeleton suggest that the inclusion body filaments may in some way be derived from the cytoskeleton This may be either from self-assembly of proteins into filaments or a degeneration or transformation of the pre-existing cytoskeleton We have investigated whether the neurofibrdlary pathology of progressive supranuclear palsy (PSP), Pick bodies of Pick disease and Lewy bodies of idiopathic Parkinson disease and diffuse Lewy body disease share epitopes with the mlcrofilament-associated protein tropomyosm 27 We found that Pick bodies, PSP tangles and some Lewy bodies m the cortex share epitopes with tropomyosm, yet Lewy bodies in idiopathic Parkinson disease do not, further distinguishing the latter mclusion Bralnstem sections were taken from two confirmed cases of progressive supranuclear palsy (range 52-65 yr) Cerebral cortex from two cases of Ptck disease (range 54-67 yr), and one case of diffuse Lewy body disease (age 70 yr) and secttons of locus coeruleus and/or substantm nlgra were obtained from nine patients with tdlopathic Parklnson disease (range 54-89 yr) Tissue was fixed
either in Bouln's fixative or 10% formalin with phosphate buffer, p H 7 0, before dehydration and embedding in paraffin Sections were cut at 6 micrometers The following antibodies were used rabbit antlsera raised to (a) chicken gizzard tropomyosln (gifts of Dr R Goldman and F Matsumura) affinity purified to tropomyosln and (b) skeletal muscle tropomyosin, and characterized as previously described 3'8 Sections were lmmunostalned with the antibodies by employing the peroxldase antlperoxldase procedure 33 with 3,3"-dlamlnobenzldlne as cosubstrate Photographs were taken on a Zelss Axlophoto equipped with Nomarskt planapochromatlc optics The neurofibrlllary pathology of progressive supranuclear palsy (Fig 1A), and Pick (Fig 1B) and diffuse Lewy body (Fig 1C) disease were stained with both antibodies to tropomyosin Lewy bodies of tchopathlc Parklnson disease remained unstained (Fig 1D) In control sections in which the primary antibody was replaced by normal goat serum, all the mcluslons remained unstained Our results show that a protein other than r, MAP2, ubtquitln or neurofilaments, and antigenically related to tropomyosin, ts present m the filamentous inclusions of progressive supranuclear palsy and Pick and diffuse Lewy body diseases Finding tropomyosin in all these inclusions implicates mlcrofilament involvement in neuroflbnllary pathologies The relatedness of the Hirano body, another impor-
Correspondence P G Galloway, Department of Pathology, 281 Locust Street, Akron, OH 44308, U S A
0006-8993/91/$03 50 (~) 1991 Elsevier Soence Pubhshers B V (Biomedical Division)
348 ~b
~r
Fig 1 Sections lmmunostamed with the affinity purified tropomyosm antibody A neurofibnllary tangles sn the bramstem of progressive supranuclear palsy B Pick bodies m Pick disease are tmmunostalned C diffuse Lewy bodies m the cortex are lmmunostamed D Lewy body in substantm mgra from idiopathic Parkmson disease is unstained (peroxldase-anti-peroxtdase, Nomarsk 0 Scale bar = 25/~m
tant intraneuronal inclusion seen in Alzhelmer patients, to tropomyosln has been shown both lmmunocytochemically3 and by 3-dimensional electron microscopy 19 The presence of tropomyosln, an actin associated protein 27, in Hlrano bodies had been suggested by the previous finding of actln I° In contrast, the presence of actln has not been observed in the neurofibrillary pathology of any disease 3 The exact pathogenetlc mechanism(s) involved in the pathogenesls of neurofibrlllary pathology have not been elucidated, despite lncreasmg knowledge as to protelnaceous composmon However, the similarity of the ultrastructural appearance of the Hlrano body and that of tropomyosln crystalhne arrays 19 suggests that the formation of these arrays may be part of a generalized irreversible crystallization of cytoskeletal proteins in Alzhelmer d~sease 2° Indeed, recent data, comparing the neurofllamentous network isolated from the giant axon of the squid (Lohgo pealel L ), compared with frontal lobe biopsies of Alzhelmer patients 21, suggest that the irreversible formation of para-crystalhne multi-protein assemblies by way of phase transmons may be a widespread mechanism m the pathogenesls of cytoskeletal alterations m Alzhelmer disease The apparent absence of tropomyosln from the Lewy
body of idiopathic Parklnson disease is lntngumg from the point of view of its apparent relatedness to the other filamentous mcluslons To date, Lewy bodies of idiopathic Parklnson disease have been shown to share ublqultm, MAP2 and neurofllament epltopes 7, as common properties with the other filamentous inclusions In contrast, Lewy bodies do not have r epltopes 7 Structurally, Lewy bodies consist of a dense central core with an array of 7-20 nm straight filaments 2 These filaments are distinct from paired helical filaments 15 of Alzhelmer disease and 15 nm straight filaments of Alzhelmer26 and Pick diseases z4 and PSP 34 The current findings further suggest that the Lewy body differs significantly from other neurofibrdlary pathologies Indeed both the cortical and subcortlcal Lewy bodies m diffuse Lewy body disease contain r 5 suggesting that idiopathic Parklnson disease may have a distract pathophyslology from those patients in which cortical structures are revolved, such as patients who have either diffuse Lewy body disease or combined Parkmson disease and Alzhelmer disease The authors thank Terl Hnat, Magdalena Mllares and Peggy Rtchey for assistance, and Mrs Mary Kay King for help preparing the manuscript
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1 Anderton, B H , Bremberg, D , Dowries, M J . Green, P J , Tomhnson, B E , Ulrich, J , Wood, J M and Kahn, J , Nature, 298 (1982) 84-86 2 Forno, L S and NOrvllle, R L , Ultrastructure of Lewy bodies m the stellate ganghon, Acta Neuropathol, 34 (1976) 183-197 3 Galloway, P , Perry, G and Gambettl, O , Hlrano body fdaments contain actm and actln-assoclated proteins, J Neuropathol Exp Neurol, 46 (1987) 185-199 4 Galloway, P , Perry, G , Kosik, K and Gambettl, P, Hlrano bodies contain tan protein, Brain Research, 403 (1987) 337-340 5 Galloway, P G , Bergeron, C and Perry, G , The presence of tau distinguishes Lewy bodies of .dlopathlc Parkmson disease from those of diffuse Lewy body disease, Neurosct Left, 100 (1989) 6-10 6 Galloway, P G , AnUgemc charactensUcs of neurofibnllary tangles in progressive supranuclear palsy, Neurosct Lett, 91 (1988) 148-153 7 Galloway, P G , Grundke-Iqbal, I , Iqbal, K and Perry, G , Lewy bodies contain epltopes both shared and distract from Alzhelmer neurofibrillary tangles, J Neuropathol Exp Neurol , 47 (1988) 171-181 8 Galloway, P G , Muivlhfll, P , Siedlak, S , M1jares, M , Kawai, M , Padget, H , Klm, R and Perry, G , Immunochermcal demonstration of tropomyosln in the neurofibnllary pathology of Alzhelmer chsease, A m J Pathol, m press 9 Gambettl, P , Velasco, M E , Dahl, D , Blgnaml, A , Roessmann, U and Slndley, S D , Alzhelmer neurofibnllary tangles an immunohlstocfiemlcal study In L AmaduccI, A N Davidson and P Antuono (Eds), Aging of the Bratn and Dementta, New York, Raven Press, Vol 13, 1980, pp 55-63 10 Goldman, J E , The association of actln with Hirano bodies, J Neuropathol Exp Neurol, 42 (1983) 146-152 11 Grundke-Iqbal, I , Johnson, A B , Wlsmewski, H M , Terry, R D and Iqbal, K , Evidence that Alzhelmer's neurofibnilary tangles originate from neurotubules, Lancet, 1 (1979) 578-580 12 Grundke-Iqbal, I , Iqbal, K , Quinlan, M , Tung, Y C , Zaidl, M S and WlSnleWSkl, H M , M.crotubule-assoclated protein tau, a component of Alzhelmer paired hehcal filaments, J B~ol Chem, 261 (1986) 6084-6089 13 Grundke-Iqbal, I , Iqbal, K , Tung, Y C , Quinlan, M , Wlsniewskl. H M and Binder, L I , Abnormal phosphorylaUon of the mlcrotubule-assoc~ated protein (tan) in Alzhelmer cytoskeletal pathology, Proc Nail Acad Sct U S A , 83 (1986) 4913-4917 14 Khachutunan, Z S , Diagnos~s of Aizheimer's disease, Arch Neurol, 42 (1985) 1097-1105 15 I(add, M , Paired helical filaments m electron microscopy of AIzhelmer disease, Nature, 197 (1963) 192-193 16 Kos~k, K S , Duff),, L K , Dowhng, M M , Abraham. C , McCiuskey, A and Selkoe, D J , Mlcrotubule-assooated proteln 2 Monoclonal antibodies demonstrate the selecUve incorporation of certain epitopes into Alzhelmer neuroflbnllary tangles, Proc Natl Acad Sct U S A , 81 (1984) 7941-7945 17 Ks~ezak-Redmg, H , Dickson, D W, Davies, P and Yen, S H , Recogmt~on of tau epltopes by anti-neurofilament antibodies that brad to Alzhe~mer neurofibnllary tangles, Proc Natl Acad Sc~ U S A , 84 (1987) 3410-3414 18 Ksiezak-Redmg, H and Yen, S H , Two monoclonal antibodies recogmze Alzheimer's neuroflbnllary tangles, neurofilament, and m~crotubule-assooated protein, J Neurochem, 48 (1987) 455-462 19 Metuzals, J , Montpetlt, V, Clapln, D F and Nelson, R F , Filamentous arrays reminiscent of tropomyosln crystals in H~rano bodies of Alzhelmer disease (Abstract) In G W Bailey ( E d ) , Proceedings of the 41st Annual Meeang of the Electron Mtcroscopy Society of American, August 8-12, 1983, Phoenix, Arizona, San Francisco Press, San Fransisco, 1983, pp 532-533 20 Metuzals, J , Montpetit, V and Clapln, D F , Organization of the neurofilamentous network, Cell Tzssue Res, 214 (1981) 455-482
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