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What mediates between β-amyloid and paired helical filaments?
Neurobiology of Aging. Vol. 10, pp. 573-574. ¢ Pergamon Press plc, 1989. Printed in the U.S.A.
developmentally-regulated mRNA in Alzheimer's disease. Submitted. 12. Hefti, F. Is Alzheimer disease caused by lack of nerve growth factor. Ann. Neurol. 13:109-110; 1983. 13. Hyman, B. T.; Van Hoesen, G. W.; Damasio, A. R.; Barnes, C. L. Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science 225:1168-1170; 1984. 14. Ihara, Y. Massive somatodendritic sprouting of cortical neurons in Alzheimer's disease. Brain Res. 459:138-144; 1988. 15. Kosik, K. S.; Orecchio, L. D.; Bakalis, S.; Neve, R. L. Developmentally regulated expression of specific tau sequences. Neuron 2:1389-1397; 1989. 16. Miller, F. D.; Geddes, J. W. Increased expression of the major embryonic a-tubulin mRNA, Tal, during neuronal regeneration, sprouting, and in Alzheimer's disease. Prog. Brain Res.; in press. 17. Miller, F. D.; Naus, C. C. G.; Durand, M.; Bloom, F. E.; Milner, R. J. Isotypes of a-tubulin are differentially regulated during neuronal maturation. J. Cell Biol. 105:3065-3073; 1987. 18. Miller, F. D.; Tetzlaff, W.; Bisby, M. A,; Fawcett, J. W.; Milner, R. J. Rapid induction of the major embryonic et-tubulin mRNA, Ted, during nerve regeneration in adult rats. J. Neurosci. 9:1452-1463; 1989. 19. Nunez, J. Immature and mature variants of MAP2 and tau proteins and neuronal plasticity. Trends Neurosci. 11:477-479; 1988. 20. Phelps, C. H., et al. Potential use of nerve growth factor to treat
0197-4580/89 $3.00 ~ .00
Alzheimer's disease. Neurobiol. Aging 10:205-207; 1989. 21. Probst, A.; Basler, V.; Bron, B.; Ulrich, J. Neuritic plaques in senile dementia of the Alzheimer type: a Golgi analysis in the hippocampal region. Brain Res. 268:249-254; 1983. 22. Probst, A.; Brunnschweiler, H.; Lautenschlager, C.; Ulrich, J. A special type of senile plaque, possibly an initial stage. Acta Neuropathol. (Berl.) 74:133-141; 1987. 23. Ramon y Cajal, S. Degeneration and regeneration of the nervous system (Translated and edited by Raoul M. May). London: Oxford University Press; 1928. 24. Scheibel, A. B.; Tomiyasu, U. Dendritic sprouting in Alzheimer's presenile dementia. Exp. Neurol. 60:1-8; 1978. 25. Skene, J. H. P.; Willard, M. Axonally transported proteins associated with axon growth in rabbit central and peripheral nervous systems. J. Cell Biol. 89:96-103; 1981. 26. Walicke, P. A. Novel neurotrophic factors, receptors, and oncogenes. Annu. Rev. Neurosci. 12:103-126; 1989. 27. Whitson, J. S.; Selkoe, D. J.; Cotman, C. W. Amyloid beta protein enhances the survival of hippocampal neurons in vitro. Science 243:1488-1490; 1989. 28. Wolozin, B. L.; Scicutella, A.; Davies, P. Re-expression of a developmentally regulated antigen in Down Syndrome and Alzheimer disease. Proc. Natl. Acad. Sci. USA 85:6202-6206; 1988.
What Mediates Between 13-Amyloid and Paired Helical Filaments?
YASUO IHARA
Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashiku, Tokyo 173 Japan
13-Amyloid precedes paired helical filaments (PHF), and both appear to be relatively independent alterations, contrary to the previous view. One of the mediators between 13-amyloid and PHF should be a trophic factor(s). Unbalanced trophic activities in the AD brain result in massive sprouting of vulnerable neurons, leading to their exhaustion and death.
THE article written by Butcher and Woolf has illuminated a new aspect of Alzheimer's disease (AD). Their title apparently contradicts a widely held view, but one without any evidence: that neurons in the AD brain die because of the lack of a specific trophic factor(s) [see (1)]. We have reached a hypothesis similar to Butcher and Woolf's but by different means, and offer some speculation on the pathogenesis and progression of AD. Recent studies on young to aged Down's syndrome cases have revealed the sequence of the appearance of AD lesions: diffuse plaque, neuritic plaque, neurofibrillary tangle/curly fiber, and amyloid angiopathy, in this order [(6,10), see also (3)]. Thus, diffuse plaque appears to be the earliest occurring lesion in the D o w n ' s syndrome brain; this should also be the case in the AD brain. Diffuse plaque is defined as diffusely stained, 13-immunoreactive areas without dystrophic neurites (16,17). EM shows in these 13-immunoreactive areas the presence of apparently normal neuropih On closer examination, some of the membranous profiles are very indistinct (presumably due to membrane lysis) and seem to be accompanied by a few amyloid fibrils in the extracellular space (Yamaguchi, personal communication). Perhaps these represent the earliest stage of amyloid fibrils, which are made of 13 protein precursor or its larger fragments.
Using an improved method (9), we found this type of 13-plaque to be far more widespread throughout the AD brain than previously thought. Diffuse plaques are present not only in the cortex, but also in the basal ganglia, brainstem, cerebellum, and even in the spinal cord (12). Thus, 13 deposition seems to occur throughout CNS of AD. Furthermore, this method has also revealed that many aged, nondemented patients have numerous 13-plaques, but few tangles in the neocortex (5,6). D o w n ' s syndrome patients exhibiting many 13-plaques, but few tangles, did not appear to show any further mental deterioration (3). Thus, it seems to me that 13 deposition per se does not cause any clinically overt manifestations. Mental deterioration appears to be much more related to the appearance of neuritic plaque or tangle/curly fiber, but not to the presence of 13-amyloid. Thus, although 13 deposition per se should be linked to AD pathogenesis, abnormal neuritic growth must be the cause of dementia, the central symptom of AD. In other words, we should distinguish two stages of AD progression: 13 deposition throughout CNS in the early stage of AD that is subclinical, and tan deposition in the cerebral cortex in the late stage that is clinically overt. It should be noted that, although 13 deposition occurs throughout CNS, accompanying tau/PHF deposition occurs exclusively in the cortex, a site that can account for the major
574
IHARA
symptoms of AD. It seems to take several years for neuritic plaques and tangles to appear following the formation of diffuse plaques (3,10). This unusually long incubation time suggests that 13 and tau coupling should not be tight but rather loose. It has been shown by immunocytochemistry that only a very minor fraction of 13-plaques are associated with tau-immunoreactive neurites. In addition, our recent extensive immunocytochemical studies on approximately 200 autopsy cases show that the localization of 13-plaques and tau-immunoreactive neurites are distinct from each other, with the former being abundant in the neocortex, and the latter much more so in the hippocampus and the entorhinal cortex (Kuzuhara and Ihara, unpublished data). This strongly suggests that deposition of 13-protein precursor or its fragments, including 13-protein, does not directly induce abnormal (tau-immunoreactive) neuritic growth: 13 deposition and tau deposition are not so interdependent, both spatially and temporally, as previously supposed. There must be a number of steps intervening between 13 deposition and tau/PHF deposition. Now a question arises: What mediates between 13-amyloid and tau/PHF? I believe that one of the mediators may be trophic factors (8). This idea comes from our previous immunocytochemical data on neuritic plaques: Anti-MAP2 intensely stains plaque neurites, while antitubulin does not (11). This unusual dissociation pattern of MAP2 and tubulin immunoreactivities is observed in Purkinje cell dendrites in the early stages of development (2). MAP2 is concentrated in the growing tips of Purkinje cell dendrites, whereas neither tubulin nor microtubules can be demonstrated by immunostaining or electron microscopy. By analogy with the observation, we interpreted our immunocytochemical results as representing the presence of growing dendrites in the neuritic plaque (11). From this observation, we reasonably postulated that
the AD brain should have higher trophic activities compared to the normal brain. This speculation has been substantiated using neonatal rat cortical neurons: The increased level of trophic activities has been demonstrated in AD brain extract (13). This increase has further been shown to be due to lack in the AD brain of an inhibitory factor, a proteinaceous factor that should suppress the trophic activities in the normal brain (14). I do not know whether the same trophic mechanism is at work in the two distinct types of sprouting, neuritic plaques and curly fibers. In this regard, it is of particular interest to investigate whether the degree of trophic activities correlates with the number of neuritic plaques and/or the abundance of curly fibers in the AD brain. The imbalance between trophic and suppressive activities induces abnormal sprouting response, which leads to exhaustion and finally death of susceptible neurons, in particular, pyramidal cells in layers III and V of the association cortex of the AD brain. The above sprouting hypothesis further predicts similarities between AD and fetal or neonatal brains: Massive sprouting responses should result in unusual expression of fetal antigens, many of which should be cytoskeletal proteins. Presumably, A68 (15) and GQIc (7) are among such fetal antigens. 13-Amyloid and PHF formations are relatively independent, both in temporal and spatial relationships [see also (4)]. A long incubation time following 13 deposition appears to be required for PHF formation, which represents a final common pathway in the neuronal degeneration and presumably is closely related to clinical manifestations of AD. If we are going to explore therapeutic measures, one of the targets should be the breaking of this loose linkage because 13 deposition itself does not appear to cause dementia. Thus, one of the directions of future investigation should be to focus on this 13 and tau linkage.
REFERENCES 1. Appel, S. H. A unifying hypothesis for the cause of amyotrophic lateral sclerosis, Parkinsonism, and Alzheimer's disease. Ann. Neurol. 10:499-505; 1981. 2. Bernhardt, R.; Matus, A. Initial phase of dendritic growth: Evidence for the involvement of high molecular weight microtubute-associated proteins (HMWP) before the appearance of mbulin. J. Cell Biol. 92:589-593; 1982. 3. Burger, P. C.; Vogel, F. S. The development of the pathologic changes of Alzheimer's disease and senile dementia in patients with Down's syndrome. Am. J. Pathol. 73:457-476; 1973. 4. Cork, L. C.; Powers, R. E.; Selkoe, D. J.; Davies, P.; Geyer, J. J.; Price, D. L. Neurofibrillary tangles and senile plaques in aged bears. J. Neuropathol. Exp. Neurol. 47:629-641; 1988. 5. Davies, L.; Wolska, B.; Hilbich, C.; Multhaup, G.; Martins, R.; Simms, G.; Beyreuther, K.; Masters, C. L. A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: Prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques. Neurology 38:1688-1693; 1988. 6. Duyckaerts, C.; Dela~re, P.; Poulain, V.; Brion, J.-P.; Hauw, J.-J. Does amyloid precede paired helical filaments in the senile plaque? A study of 15 cases with graded intellectual status in aging and Alzheimer disease. Neurosci. Lett. 91:354-359; 1988. 7. Emory, C. R.; Ala, T. A.; Frey, W. H., II. Ganglia,side monoclonal antibody (A2B5) labels Alzheimer's neurofibrillary tangles. Neurology 37:768-772; 1987. 8. Ihara, Y. Massive somatodendritic sprouting of cortical neurons in Alzheimer's disease. Brain Res. 459:138-144; 1988. 9. Kitamoto, T.; Ogomori, K.; Tateishi, J.; Prusiner, S. B. Formic acid pretreatment enhances immunostaining of cerebral and systemic
amyloids. Lab. Invest. 57:230-236; 1987. 10. Mann, D. M. A.; Esiri, M. M. The site of the earliest lesions of Alzheimer's disease. N. Engl. J. Med. 318:789-790; 1988. 11. Nukina, N.; Ihara, Y. Immunocytochemicat study on senile plaques in Alzheimer's disease. II. Abnormal dendrites in senile plaques as revealed by antimicrotubute-associated proteins (MAPs) immunostaining. Proc. Jpn. Acad. 59B:288-292; 1983. 12. Ogomori, K.; Kitamoto, T.; Tateishi, J.; Sato, Y.; Suetsugu, M.; Abe, M. 13-proteinamyloid is widely distributed in the central nervous system of patients with Alzheimer's disease. Am. J, Pathol. 134: 243-251; 1989. 13. Uchida, Y.; Ihara, Y.; Tomonaga, M.. Alzheimer's disease brain extract stimulates the survival of cerebral cortical neurons from neonatal rats. Biochem. Biophys. Res. Commun. 150:1263-1267; 1988. 14. Uchida, Y.; Tomonaga, M. Neurotrophic action of Alzheimer's disease brain extract is due to the loss of inhibitory factors for survival and neurite formation of cerebral cortical neurons. Brain Res. 481: 190-193; 1989. 15. Wolozin, B.; Scicutella, A.; Davies, P. Reexamination of a developmentally regulated antigen in Down syndrome and Alzheimer disease. Proc. Natl. Aead. Sci. USA 85:6202-6206; 1988. 16. Yamaguchi, H.; Hirai, S.; Morimatsu, M.; Shoji, M.; lhara, Y. A variety of cerebral amyloid deposits in the brains of the Alzheimertype dementia demonstrated by 13 protein immunostaining. Acta Neuropathol. (Bed.) 76:541-549; 1988. 17. Yamaguchi, H.; Hirai, S.; Morimatsu, M.; Shoji, M.; Harigaya, Y. Diffuse type of senile plaques in the brains of Alzheimer-type dementia. Acta Neuropathol. (Bed.) 77:113-1 t9; 1988.
developmentally-regulated mRNA in Alzheimer's disease. Submitted. 12. Hefti, F. Is Alzheimer disease caused by lack of nerve growth factor. Ann. Neurol. 13:109-110; 1983. 13. Hyman, B. T.; Van Hoesen, G. W.; Damasio, A. R.; Barnes, C. L. Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science 225:1168-1170; 1984. 14. Ihara, Y. Massive somatodendritic sprouting of cortical neurons in Alzheimer's disease. Brain Res. 459:138-144; 1988. 15. Kosik, K. S.; Orecchio, L. D.; Bakalis, S.; Neve, R. L. Developmentally regulated expression of specific tau sequences. Neuron 2:1389-1397; 1989. 16. Miller, F. D.; Geddes, J. W. Increased expression of the major embryonic a-tubulin mRNA, Tal, during neuronal regeneration, sprouting, and in Alzheimer's disease. Prog. Brain Res.; in press. 17. Miller, F. D.; Naus, C. C. G.; Durand, M.; Bloom, F. E.; Milner, R. J. Isotypes of a-tubulin are differentially regulated during neuronal maturation. J. Cell Biol. 105:3065-3073; 1987. 18. Miller, F. D.; Tetzlaff, W.; Bisby, M. A,; Fawcett, J. W.; Milner, R. J. Rapid induction of the major embryonic et-tubulin mRNA, Ted, during nerve regeneration in adult rats. J. Neurosci. 9:1452-1463; 1989. 19. Nunez, J. Immature and mature variants of MAP2 and tau proteins and neuronal plasticity. Trends Neurosci. 11:477-479; 1988. 20. Phelps, C. H., et al. Potential use of nerve growth factor to treat
0197-4580/89 $3.00 ~ .00
Alzheimer's disease. Neurobiol. Aging 10:205-207; 1989. 21. Probst, A.; Basler, V.; Bron, B.; Ulrich, J. Neuritic plaques in senile dementia of the Alzheimer type: a Golgi analysis in the hippocampal region. Brain Res. 268:249-254; 1983. 22. Probst, A.; Brunnschweiler, H.; Lautenschlager, C.; Ulrich, J. A special type of senile plaque, possibly an initial stage. Acta Neuropathol. (Berl.) 74:133-141; 1987. 23. Ramon y Cajal, S. Degeneration and regeneration of the nervous system (Translated and edited by Raoul M. May). London: Oxford University Press; 1928. 24. Scheibel, A. B.; Tomiyasu, U. Dendritic sprouting in Alzheimer's presenile dementia. Exp. Neurol. 60:1-8; 1978. 25. Skene, J. H. P.; Willard, M. Axonally transported proteins associated with axon growth in rabbit central and peripheral nervous systems. J. Cell Biol. 89:96-103; 1981. 26. Walicke, P. A. Novel neurotrophic factors, receptors, and oncogenes. Annu. Rev. Neurosci. 12:103-126; 1989. 27. Whitson, J. S.; Selkoe, D. J.; Cotman, C. W. Amyloid beta protein enhances the survival of hippocampal neurons in vitro. Science 243:1488-1490; 1989. 28. Wolozin, B. L.; Scicutella, A.; Davies, P. Re-expression of a developmentally regulated antigen in Down Syndrome and Alzheimer disease. Proc. Natl. Acad. Sci. USA 85:6202-6206; 1988.
What Mediates Between 13-Amyloid and Paired Helical Filaments?
YASUO IHARA
Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashiku, Tokyo 173 Japan
13-Amyloid precedes paired helical filaments (PHF), and both appear to be relatively independent alterations, contrary to the previous view. One of the mediators between 13-amyloid and PHF should be a trophic factor(s). Unbalanced trophic activities in the AD brain result in massive sprouting of vulnerable neurons, leading to their exhaustion and death.
THE article written by Butcher and Woolf has illuminated a new aspect of Alzheimer's disease (AD). Their title apparently contradicts a widely held view, but one without any evidence: that neurons in the AD brain die because of the lack of a specific trophic factor(s) [see (1)]. We have reached a hypothesis similar to Butcher and Woolf's but by different means, and offer some speculation on the pathogenesis and progression of AD. Recent studies on young to aged Down's syndrome cases have revealed the sequence of the appearance of AD lesions: diffuse plaque, neuritic plaque, neurofibrillary tangle/curly fiber, and amyloid angiopathy, in this order [(6,10), see also (3)]. Thus, diffuse plaque appears to be the earliest occurring lesion in the D o w n ' s syndrome brain; this should also be the case in the AD brain. Diffuse plaque is defined as diffusely stained, 13-immunoreactive areas without dystrophic neurites (16,17). EM shows in these 13-immunoreactive areas the presence of apparently normal neuropih On closer examination, some of the membranous profiles are very indistinct (presumably due to membrane lysis) and seem to be accompanied by a few amyloid fibrils in the extracellular space (Yamaguchi, personal communication). Perhaps these represent the earliest stage of amyloid fibrils, which are made of 13 protein precursor or its larger fragments.
Using an improved method (9), we found this type of 13-plaque to be far more widespread throughout the AD brain than previously thought. Diffuse plaques are present not only in the cortex, but also in the basal ganglia, brainstem, cerebellum, and even in the spinal cord (12). Thus, 13 deposition seems to occur throughout CNS of AD. Furthermore, this method has also revealed that many aged, nondemented patients have numerous 13-plaques, but few tangles in the neocortex (5,6). D o w n ' s syndrome patients exhibiting many 13-plaques, but few tangles, did not appear to show any further mental deterioration (3). Thus, it seems to me that 13 deposition per se does not cause any clinically overt manifestations. Mental deterioration appears to be much more related to the appearance of neuritic plaque or tangle/curly fiber, but not to the presence of 13-amyloid. Thus, although 13 deposition per se should be linked to AD pathogenesis, abnormal neuritic growth must be the cause of dementia, the central symptom of AD. In other words, we should distinguish two stages of AD progression: 13 deposition throughout CNS in the early stage of AD that is subclinical, and tan deposition in the cerebral cortex in the late stage that is clinically overt. It should be noted that, although 13 deposition occurs throughout CNS, accompanying tau/PHF deposition occurs exclusively in the cortex, a site that can account for the major
574
IHARA
symptoms of AD. It seems to take several years for neuritic plaques and tangles to appear following the formation of diffuse plaques (3,10). This unusually long incubation time suggests that 13 and tau coupling should not be tight but rather loose. It has been shown by immunocytochemistry that only a very minor fraction of 13-plaques are associated with tau-immunoreactive neurites. In addition, our recent extensive immunocytochemical studies on approximately 200 autopsy cases show that the localization of 13-plaques and tau-immunoreactive neurites are distinct from each other, with the former being abundant in the neocortex, and the latter much more so in the hippocampus and the entorhinal cortex (Kuzuhara and Ihara, unpublished data). This strongly suggests that deposition of 13-protein precursor or its fragments, including 13-protein, does not directly induce abnormal (tau-immunoreactive) neuritic growth: 13 deposition and tau deposition are not so interdependent, both spatially and temporally, as previously supposed. There must be a number of steps intervening between 13 deposition and tau/PHF deposition. Now a question arises: What mediates between 13-amyloid and tau/PHF? I believe that one of the mediators may be trophic factors (8). This idea comes from our previous immunocytochemical data on neuritic plaques: Anti-MAP2 intensely stains plaque neurites, while antitubulin does not (11). This unusual dissociation pattern of MAP2 and tubulin immunoreactivities is observed in Purkinje cell dendrites in the early stages of development (2). MAP2 is concentrated in the growing tips of Purkinje cell dendrites, whereas neither tubulin nor microtubules can be demonstrated by immunostaining or electron microscopy. By analogy with the observation, we interpreted our immunocytochemical results as representing the presence of growing dendrites in the neuritic plaque (11). From this observation, we reasonably postulated that
the AD brain should have higher trophic activities compared to the normal brain. This speculation has been substantiated using neonatal rat cortical neurons: The increased level of trophic activities has been demonstrated in AD brain extract (13). This increase has further been shown to be due to lack in the AD brain of an inhibitory factor, a proteinaceous factor that should suppress the trophic activities in the normal brain (14). I do not know whether the same trophic mechanism is at work in the two distinct types of sprouting, neuritic plaques and curly fibers. In this regard, it is of particular interest to investigate whether the degree of trophic activities correlates with the number of neuritic plaques and/or the abundance of curly fibers in the AD brain. The imbalance between trophic and suppressive activities induces abnormal sprouting response, which leads to exhaustion and finally death of susceptible neurons, in particular, pyramidal cells in layers III and V of the association cortex of the AD brain. The above sprouting hypothesis further predicts similarities between AD and fetal or neonatal brains: Massive sprouting responses should result in unusual expression of fetal antigens, many of which should be cytoskeletal proteins. Presumably, A68 (15) and GQIc (7) are among such fetal antigens. 13-Amyloid and PHF formations are relatively independent, both in temporal and spatial relationships [see also (4)]. A long incubation time following 13 deposition appears to be required for PHF formation, which represents a final common pathway in the neuronal degeneration and presumably is closely related to clinical manifestations of AD. If we are going to explore therapeutic measures, one of the targets should be the breaking of this loose linkage because 13 deposition itself does not appear to cause dementia. Thus, one of the directions of future investigation should be to focus on this 13 and tau linkage.
REFERENCES 1. Appel, S. H. A unifying hypothesis for the cause of amyotrophic lateral sclerosis, Parkinsonism, and Alzheimer's disease. Ann. Neurol. 10:499-505; 1981. 2. Bernhardt, R.; Matus, A. Initial phase of dendritic growth: Evidence for the involvement of high molecular weight microtubute-associated proteins (HMWP) before the appearance of mbulin. J. Cell Biol. 92:589-593; 1982. 3. Burger, P. C.; Vogel, F. S. The development of the pathologic changes of Alzheimer's disease and senile dementia in patients with Down's syndrome. Am. J. Pathol. 73:457-476; 1973. 4. Cork, L. C.; Powers, R. E.; Selkoe, D. J.; Davies, P.; Geyer, J. J.; Price, D. L. Neurofibrillary tangles and senile plaques in aged bears. J. Neuropathol. Exp. Neurol. 47:629-641; 1988. 5. Davies, L.; Wolska, B.; Hilbich, C.; Multhaup, G.; Martins, R.; Simms, G.; Beyreuther, K.; Masters, C. L. A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: Prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques. Neurology 38:1688-1693; 1988. 6. Duyckaerts, C.; Dela~re, P.; Poulain, V.; Brion, J.-P.; Hauw, J.-J. Does amyloid precede paired helical filaments in the senile plaque? A study of 15 cases with graded intellectual status in aging and Alzheimer disease. Neurosci. Lett. 91:354-359; 1988. 7. Emory, C. R.; Ala, T. A.; Frey, W. H., II. Ganglia,side monoclonal antibody (A2B5) labels Alzheimer's neurofibrillary tangles. Neurology 37:768-772; 1987. 8. Ihara, Y. Massive somatodendritic sprouting of cortical neurons in Alzheimer's disease. Brain Res. 459:138-144; 1988. 9. Kitamoto, T.; Ogomori, K.; Tateishi, J.; Prusiner, S. B. Formic acid pretreatment enhances immunostaining of cerebral and systemic
amyloids. Lab. Invest. 57:230-236; 1987. 10. Mann, D. M. A.; Esiri, M. M. The site of the earliest lesions of Alzheimer's disease. N. Engl. J. Med. 318:789-790; 1988. 11. Nukina, N.; Ihara, Y. Immunocytochemicat study on senile plaques in Alzheimer's disease. II. Abnormal dendrites in senile plaques as revealed by antimicrotubute-associated proteins (MAPs) immunostaining. Proc. Jpn. Acad. 59B:288-292; 1983. 12. Ogomori, K.; Kitamoto, T.; Tateishi, J.; Sato, Y.; Suetsugu, M.; Abe, M. 13-proteinamyloid is widely distributed in the central nervous system of patients with Alzheimer's disease. Am. J, Pathol. 134: 243-251; 1989. 13. Uchida, Y.; Ihara, Y.; Tomonaga, M.. Alzheimer's disease brain extract stimulates the survival of cerebral cortical neurons from neonatal rats. Biochem. Biophys. Res. Commun. 150:1263-1267; 1988. 14. Uchida, Y.; Tomonaga, M. Neurotrophic action of Alzheimer's disease brain extract is due to the loss of inhibitory factors for survival and neurite formation of cerebral cortical neurons. Brain Res. 481: 190-193; 1989. 15. Wolozin, B.; Scicutella, A.; Davies, P. Reexamination of a developmentally regulated antigen in Down syndrome and Alzheimer disease. Proc. Natl. Aead. Sci. USA 85:6202-6206; 1988. 16. Yamaguchi, H.; Hirai, S.; Morimatsu, M.; Shoji, M.; lhara, Y. A variety of cerebral amyloid deposits in the brains of the Alzheimertype dementia demonstrated by 13 protein immunostaining. Acta Neuropathol. (Bed.) 76:541-549; 1988. 17. Yamaguchi, H.; Hirai, S.; Morimatsu, M.; Shoji, M.; Harigaya, Y. Diffuse type of senile plaques in the brains of Alzheimer-type dementia. Acta Neuropathol. (Bed.) 77:113-1 t9; 1988.