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Pathological changes in the brain of a patient with familial Alzheimer's disease having a missense mutation at codon 717 in the amyloid precursor protein gene
Neuroscience Letters, 137 (1992) 225-228 © 1992 Elsevier Scientific Publishers Ireland Ltd. All rights reserved 0304-3940/92/$ 05.00
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NSL 08501
Pathological changes in the brain of a patient with familial Alzheimer's disease having a missense mutation at codon 717 in the amyloid precursor protein gene D.M.A. Mann a, D. Jones a, J.S. Snowden b, D. N e a r y b and J. H a r d y c aDepartment of Pathological Sciences, Division of Molecular Pathology, University of Manchester, Manchester (UK), bDepartmentof Neurology, The Royal Infirmary, Manchester ( UK) andCDepartmentof Biochemistry and Molecular Genetics, St. Mary's Hospital Medical School London ( UK) (Received 18 November 1991; Revised version received 18 December 1991; Accepted 23 December 1991)
Key words: Familial Alzheimer's disease; Amyloid precursor protein; Mutation The brain of a 61-year-old patient with familial Alzheimer's disease, showing a missense (valine-~glycine) mutation at codon 717 of the amyloid precursor gene, has been examined at postmortem. Sections of brain showed pathological features entirely typical of Alzheimer's disease with no unusual characteristics. It seems therefore that this particular mutation is indeed pathogenic and that the altered amyloid precursor protein resulting from expression of this mutation is processed in a way that triggers or promotes the pathological cascade of Alzheimer's disease.
The deposition of an amyloidogenic protein, known as fl or A4 (fl/A4) protein, forms an integral part of the molecular pathology of the senile plaque, this being one of the characteristic hallmarks of Alzheimer's disease (AD). fl/A4 protein is accumulated within the brain as a result of an unusual proteolytic cleavage [4] of a larger precursor protein, fl amyloid precursor protein (flAPP), which is present as a trans-membrane molecule with a small intracytoplasmic domain and a large and possibly secretory external domain [12]. This protein is encoded by a gene located on the distal part of the long arm of chromosome 21 [7, 12, 27]. Genetic linkage between the fl amyloid gene and inherited disease has been demonstrated collectively within the pedigrees of a large number of cases of familial AD [5, 24], though within these various pedigrees it has been observed that a substantial proportion of the total derived peak lod score was generated by just one or two families [24]. Hence, subsequent genetic analysis [6] on one of these particular families (pedigree number F23 of Goate et al. [5]) has shown an amino acid substitution (valine--fisoleucine) at codon 717 of the flAPP suggesting that this mutation is likely to account for the genetic linkage detected on chromosome 21. Similar analyses of other unrelated families Correspondence: D.M.A. Mann, Department of Pathological Sciences, Division of Molecular Pathology, University of Manchester, Manchester M13 9PT, UK.
in America [6] and Japan [21] has also demonstrated this same val-~ile substitution and although all affected patients have become clinically demented, in only a few instances has it been possible to confirm the diagnosis of AD at autopsy. Certain problems have occurred in relationship to the autopsied member of F23 [6] since at postmortem not only were numerous plaques and tangles typically present within the neocortex and hippocampus but, uncharacteristically, there were inclusions similar to Lewy bodies within surviving cortical and brainstem neurones [9]. In autopsied patients from the Japanese and American families [21] findings typical and solely of AD were seen at autopsy (see ref. 9). Most recently genetic analysis of a further American family [20] has revealed a different mutation (valine-~phenylalanine) but again at codon 717, in 4 affected members; a pathological picture typical of AD was seen in 3 individuals at autopsy. Analysis of a further British family, F19 [1] has detected yet another mutation at codon 717, but here resulting in a valine~glycine substitution. Hence, it appears that certain inherited forms of AD are associated with several different mutations at codon 717 of the APP molecule and that there may be variations in the pathological phenotype resulting from such mutations. In this study we report that the val--~gly substitution in family F19 is associated (in one patient at least) with a pathological pattern that is entirely typical
226
Fig. 1. Pathologicalchanges in the brain of a 61-year-oldpatient with familial Alzheimer'sdisease. The hippocampus (a, b) shows numerous amyloid deposits within area CAI (a) with many of these containing dystrophic neurites (b); nerve cells containing neurofibrillarytangles are also common in this region. Numerous amyloid deposits are also present within the temporal cortex (c) and cerebellarcortex (d), a, c, d: Methenamine silver; b: Palmgren silver. Final magnifications: a, b x 285; c x 46: d x 115.
of AD and shows no specific features that would differentiate this case from any other case of AD that has passed through our laboratory investigations. The patient was a 61-year-old woman from a family [1] showing a multiple affliction of members over several generations; mode of inheritance being of an autosomal dominant pattern [1]. The brain (1230 g) was obtained fresh at autopsy, with half being deep frozen and half fixed by immersion in 10% neutral formalin for 3 4 weeks. Blocks were cut from multiple cortical, subcortical, mid brain, brainstem and cerebellar regions and processed routinely into paraffin wax. Sections (5/~m) were stained by conventional neurohistological techniques including Palmgren silver [2] and Methenamine silver [8] methods (see refs. 15 and 18 for details) for neuritic plaques and neurofibrillary tangles and deposits of fl/A4 protein, respectively. These methods were augmented by conventional immunohistochemical staining (avidin-biotin-peroxidase) using primary antibodies against A4 protein [3], P H F protein, tau (Sigma), ubiquitin (Dako) and GFAP (Sigma) (see refs. 15 and 18 for details). Sections of brain showed mostly 'diffuse' but sometimes 'cored' deposits of ]J/A4 protein throughout the cerebral cortex, hippocampus and amygdala, corpus striatum and thalamus, hypothalamus and cerebellar cortex. In the cerebral cortex, hippocampus and amygdala many of these deposits also contained neurites (i.e. were 'neuritic' or 'senile' plaques). In these regions, and other areas such as nucleus basalis, dorsal raphe and locus caeruleus, neurofibrillary tangles (NFT) were corn-
227 M U T A T I O N S IN GENES OT~ THAN APP
CODON 717 MUTATIONS
ALTERED
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~
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NON-GENETIC (enviromental)
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~ ? S
~ SENILE
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NE~OFIBRIL~Y T~GLES
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NERVE C E L L DEATH
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Fig.2.PossiblepathogeneticpathwaysforthecausesandprogressionofthepathologicalchangesofAhheimer'disease. s mon. No intraneuronal inclusions other than N F T were seen. Immunohistochemistry demonstrated a typical anti-PHF, anti-tau and anti-ubiquitin immunoreactivity to N F T and plaques also typically stained with anti-tau, anti-ubiquitin and anti-GFAP. Again, using immunochemical methods no intraneuronal inclusions other than N F T were seen. Anti-A4 immunostaining revealed severe congophilic angiopathy within meningeal vessels overlying cerebellar and occipital cortices though this was much less severe in other brain regions. These pathological changes (represented by Fig. 1) are thus entirely typical of AD and display no unusual characteristics. The implication of this present study is that this particular mutation within codon 717 of the APP molecule is probably pathogenic and leads to a pathological outcome that is entirely that of AD. This result appears to be the same in most of the other mutations of codon 717 [20, 21], though apparently not so in all [6, 9]. How the pathological cascade of AD is brought about by this mutation is not clear though it is likely that it is associated with some abberation in the metabolism of APP. The fact that there are (so far 3) different mutations at codon 717 implies that neither hydrophobicity nor bulk are critical to the altered processing. Moreover, it has been shown [10] that in the case of the val---)ile substitution, at least, no change in the rate of APP expression is associated with this defect. Hence it is possible that in some way the altered APP is prevented from being processed via normal metabolic pathways (which involve a cleavage across the flA4 sequence [4]) and is diverted along a subsidiary pathway which is perhaps normally inhibited but
which ultimately leads to the unusual and excessive formation and accumulation of fl/A4 peptide. Other familial forms of AD (not involving a codon 717 mutation or a mutation in other parts of the APP molecule), Down's syndrome (DS), as well as non-genetic (environmental) causes might all bring about the same, or a similar, APP processing defect and cause fl/A4 to accumulate (Fig. 2). Whether deposition of fl/A4, per se, is sufficient to trigger the rest of the pathological cascade (Fig. 2) is less clear since it is now well known that deposition offl/A4 can occur in the absence of neuritic changes and N F T formation in areas such as striatum [22] and cerebellum [11, 14, 23] in both AD and DS and even within the cerebral cortex and hippocampus in conditions other than AD (and DS) [13, 17, 19, 26]. Hence, PHF formation may proceed in parallel to, but not necessarily as a direct consequence of, fl/A4 formation. It is possible that it is a different fragment of the APP molecule, released during its cleavage that is responsible for, or modulates, PHF formation. Whatever the factor that triggers PHF formation might be, it seems clear that it is an entity that is specific for AD and perhaps more importantly one that is specifically produced by the cerebral cortex in AD, or if it is produced in other regions (e.g. cerebellum) it does not affect local neurones in the same way. The fact that the APP molecule is glycosylated [12] and observations that unusual and excessive accumulations of glycoproteins occur within the cerebral cortical, but not the cerebellar cortical, amyloid deposits, in AD and DS [14, 16, 18, 25] suggest that oligosaccharides, possibly derived from APE might mediate the neuritic changes.
228 1 Chartier-Harlin, M.C., Crawford, F., Houlden, H., Warren, A., Hughes, D., Fidani, L., Goate, A., Rossor, M., Roques, P., Hardy, J. and Mullan, M. Mutations at codon 717 of the ,8-amyloid precursor protein gene cause Alzheimer's disease, Nature, 353 (1991) 844-846. 2 Cross, R.B., Demonstration of neurofibrillary tangles in paraffin section a quick and simple method using Palmgren's technique, Med. Lab. Sci., 39 (1982) 67 69. 3 Davies, L., Wolska, B., Hilbich, C., Multhaup, G., Martins, R., Simms, G., Beyreuther, K. and Masters, C.L., A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathological techniques, Neurology 38 (1988) 1688-1693. 4 Esch, F.S., Helm, P.S., Beattie, E.C., Blancher, R.W., Culwell, A.R., Oltersdorf, T., McClure, D. and Ward, P.J., Cleavage of amyloid ,8 peptide during constitutive processing of its precursor, Science, 248 (1990) 1122- 1124. 5 Goate, A., Owen, M.J., James, L.A., Mullan, M.J., Rossor, M.N., Haynes, A.R., Farrall, M., Lai, L.Y.C., Roques, P., Williamson, R. and Hardy, J.A., Predisposing locus for Alzheimer's disease on chromosome 21, Lancet, i (1989) 352-355. 6 Goate, A., Chartier-Harlin, M.C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Gioffra, L., Haynes, A., Irving, N., James, L., Mant, R., Newton, P., Rooke, K., Roques, P., Talbot, C., Pericak-Vance, M., Roses, A., Williamson, R., Rossor, M., Owen, M. and Hardy, J.A., Segregation ofa missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease, Nature, 349 (1991) 704-706. 7 Goldgaber, D., Lerman, M.I., McBride, O.W., Saffioti, U. and Gajdusek, D.C., Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease, Science, 235 (1987) 877--880. 8 Haga, C., Yamaguchi, I., lkeda, K. and Kosaka, K., PAM modified silver stain for senile plaques: comparison with ,8 protein immunostaining, Dementia, 3 (1989) 417-422. 9 Hardy, J.A., Mullan, M., Chartier-Harlin, M.C. et al., Molecular classification of Alzheimer's disease, Lancet, 337 (1991 ) 1342-1342. 10 Harrison, P.J., Barton, A.J. and Pearson, R.C.A., Expression of amyloid ,8 protein precursor mRNAs in familial Alzheimer's disease, Neurorep., 2 (1991) 152 154. 11 Joachim, C.L., Morris, J.H. and Selkoe, D.J., Diffuse senile plaques occur commonly in the cerebellum in Alzheimer's disease, Am. J. Pathol., 135 (1989) 309 319. 12 Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J.M., Masters, C.L., Grzeschik, K.H., Multhaup, G., Beyreuther, K. and MullerHill, B., The precursor of Alzheimer's disease A4 protein resembles a cell surface receptor, Nature, 325 (1987) 733 736. 13 Mann, D.M.A. and Jones, D., Deposition of amyloid protein in the brains of persons with dementing disorders other than Alzheimer's disease and Down's syndrome, Neurosci. Lett., 109 (1990) 68 75. 14 Mann, D.M.A., Jones, D., Prinja, D. and Purkiss, M.S., The pre-
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valence of amyloid (A4) protein deposits within the cerebral and cerebellar cortex in Down's syndrome and Alzheimer's disease, Acta Neuropathol., 80 (1990) 318-327. Mann, D.M.A., Brown, A., Prinja, D. and Davies, C.A., Immunocytochemical and lectin histochemical studies of senile plaques in the brains of non-demented persons of different ages, Neuropathol. Appl. Neurobiol., 16 (1990) 17 25. Mann, D.M.A., Bonshek, R.E., Marcyniuk, B., Stoddart, R.W. and Torgerson, E., Saccharides of senile plaques and neurofibrillary tangles in Alzheimer's disease, Neurosci Lett., 85 (1988) 15-24. Mann, D.M.A., Jones, D., South, P.W., Snowden, J.S. and Neary, D., Deposition of amyloid fl protein in non-Alzheimer dementias; evidence for a neuronal origin of parenchymal deposits offl protein in neurodegenerative disease, Acta Neuropathol., in press. Mann, D.M.A., Brown, A., Prinja, D., Davies, C.A., Landon, M., Masters, C.L. and Beyreuther, K., An analysis of the morphology of senile plaques in Down's syndrome patients of different ages using immunocytochemical and lectin histochemical techniques, Neuropathol. Appl. Neurobiol., 15 (1989) 317 329. Mastaglia, F., Masters, C.L., Beyreuther, K. and Kakulas, B., Deposition of amyloid (A4) protein in the cerebral cortex in Parkinson's disease, Alzheimer's Dis. Assoc. Disord., 2 (1988) 254. Murrell, J., Farlow, M., Ghetti, B. and Benson, M.D., A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease, Science, in press. Narose, S., Igarashi, S., Aoki, K., Kaneko, K., Iihara, K., Kobayashi, H., Inozuka, T., Shimizu, T., Kojima, T., Miyatake, T. and Tsuji, S., Mis-sense mutation val--,ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease, Lancet, 337 (1991) 978-979. Suenaga, T., Hirano, A., Llena, J.F., Yen, S.-H. and Dickson, D.W., Modified Bielschowsky staining and immunohistochemicat studies on striatal plaques in Alzheimer's disease, Acta Neuropathol., 80 (1990) 280 286. Suenaga, T., Hirano, A., Llena, J.F., Ksiesak-Reding, H., Yen, S.-H. and Dickson, D.W., Modified Bielschowsky staining and immunocytochemical studies on cerebellar plaques in Alzheimer's disease, J. Neuropathol. Exp. Neurol., 49 (1990) 31-40. St George Hyslop, P.H., Haines, J.L., Farrer, L.A. et al., Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder, Nature, 347 (1990) 194-197. Szumanska, G., Vorbrodt, A.W., Mandybur, T.I. and Wisniewski, H.M., Lectin histochemistry of plaques and tangles in Alzheimer's disease, Acta Neuropathol., 73 (1987) 1-I 1. Tan, N., Mastaglia, F., Masters, C.L., Beyreuther, K. and Kakulas, B.A., Amyloid (A4) deposition in brain in progressive supranuclear palsy (PSP), Alzheimer's Dis. Assoc. Disord., 2 (1988) 264. Tanzi, R.E., Gusella, J.F., Watkins, P.C., Bruns, G.A.P., St George-Hyslop, P., Van Keuren, M.L., Patterson, D., Pagan, S., Kurnit, D.M. and Neve, R.L., Amyloid 8 protein gene: cDNA, mRNA distribution and genetic linkage near the Alzheimer locus, Science, 235 (1987) 880-884.
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Pathological changes in the brain of a patient with familial Alzheimer's disease having a missense mutation at codon 717 in the amyloid precursor protein gene D.M.A. Mann a, D. Jones a, J.S. Snowden b, D. N e a r y b and J. H a r d y c aDepartment of Pathological Sciences, Division of Molecular Pathology, University of Manchester, Manchester (UK), bDepartmentof Neurology, The Royal Infirmary, Manchester ( UK) andCDepartmentof Biochemistry and Molecular Genetics, St. Mary's Hospital Medical School London ( UK) (Received 18 November 1991; Revised version received 18 December 1991; Accepted 23 December 1991)
Key words: Familial Alzheimer's disease; Amyloid precursor protein; Mutation The brain of a 61-year-old patient with familial Alzheimer's disease, showing a missense (valine-~glycine) mutation at codon 717 of the amyloid precursor gene, has been examined at postmortem. Sections of brain showed pathological features entirely typical of Alzheimer's disease with no unusual characteristics. It seems therefore that this particular mutation is indeed pathogenic and that the altered amyloid precursor protein resulting from expression of this mutation is processed in a way that triggers or promotes the pathological cascade of Alzheimer's disease.
The deposition of an amyloidogenic protein, known as fl or A4 (fl/A4) protein, forms an integral part of the molecular pathology of the senile plaque, this being one of the characteristic hallmarks of Alzheimer's disease (AD). fl/A4 protein is accumulated within the brain as a result of an unusual proteolytic cleavage [4] of a larger precursor protein, fl amyloid precursor protein (flAPP), which is present as a trans-membrane molecule with a small intracytoplasmic domain and a large and possibly secretory external domain [12]. This protein is encoded by a gene located on the distal part of the long arm of chromosome 21 [7, 12, 27]. Genetic linkage between the fl amyloid gene and inherited disease has been demonstrated collectively within the pedigrees of a large number of cases of familial AD [5, 24], though within these various pedigrees it has been observed that a substantial proportion of the total derived peak lod score was generated by just one or two families [24]. Hence, subsequent genetic analysis [6] on one of these particular families (pedigree number F23 of Goate et al. [5]) has shown an amino acid substitution (valine--fisoleucine) at codon 717 of the flAPP suggesting that this mutation is likely to account for the genetic linkage detected on chromosome 21. Similar analyses of other unrelated families Correspondence: D.M.A. Mann, Department of Pathological Sciences, Division of Molecular Pathology, University of Manchester, Manchester M13 9PT, UK.
in America [6] and Japan [21] has also demonstrated this same val-~ile substitution and although all affected patients have become clinically demented, in only a few instances has it been possible to confirm the diagnosis of AD at autopsy. Certain problems have occurred in relationship to the autopsied member of F23 [6] since at postmortem not only were numerous plaques and tangles typically present within the neocortex and hippocampus but, uncharacteristically, there were inclusions similar to Lewy bodies within surviving cortical and brainstem neurones [9]. In autopsied patients from the Japanese and American families [21] findings typical and solely of AD were seen at autopsy (see ref. 9). Most recently genetic analysis of a further American family [20] has revealed a different mutation (valine-~phenylalanine) but again at codon 717, in 4 affected members; a pathological picture typical of AD was seen in 3 individuals at autopsy. Analysis of a further British family, F19 [1] has detected yet another mutation at codon 717, but here resulting in a valine~glycine substitution. Hence, it appears that certain inherited forms of AD are associated with several different mutations at codon 717 of the APP molecule and that there may be variations in the pathological phenotype resulting from such mutations. In this study we report that the val--~gly substitution in family F19 is associated (in one patient at least) with a pathological pattern that is entirely typical
226
Fig. 1. Pathologicalchanges in the brain of a 61-year-oldpatient with familial Alzheimer'sdisease. The hippocampus (a, b) shows numerous amyloid deposits within area CAI (a) with many of these containing dystrophic neurites (b); nerve cells containing neurofibrillarytangles are also common in this region. Numerous amyloid deposits are also present within the temporal cortex (c) and cerebellarcortex (d), a, c, d: Methenamine silver; b: Palmgren silver. Final magnifications: a, b x 285; c x 46: d x 115.
of AD and shows no specific features that would differentiate this case from any other case of AD that has passed through our laboratory investigations. The patient was a 61-year-old woman from a family [1] showing a multiple affliction of members over several generations; mode of inheritance being of an autosomal dominant pattern [1]. The brain (1230 g) was obtained fresh at autopsy, with half being deep frozen and half fixed by immersion in 10% neutral formalin for 3 4 weeks. Blocks were cut from multiple cortical, subcortical, mid brain, brainstem and cerebellar regions and processed routinely into paraffin wax. Sections (5/~m) were stained by conventional neurohistological techniques including Palmgren silver [2] and Methenamine silver [8] methods (see refs. 15 and 18 for details) for neuritic plaques and neurofibrillary tangles and deposits of fl/A4 protein, respectively. These methods were augmented by conventional immunohistochemical staining (avidin-biotin-peroxidase) using primary antibodies against A4 protein [3], P H F protein, tau (Sigma), ubiquitin (Dako) and GFAP (Sigma) (see refs. 15 and 18 for details). Sections of brain showed mostly 'diffuse' but sometimes 'cored' deposits of ]J/A4 protein throughout the cerebral cortex, hippocampus and amygdala, corpus striatum and thalamus, hypothalamus and cerebellar cortex. In the cerebral cortex, hippocampus and amygdala many of these deposits also contained neurites (i.e. were 'neuritic' or 'senile' plaques). In these regions, and other areas such as nucleus basalis, dorsal raphe and locus caeruleus, neurofibrillary tangles (NFT) were corn-
227 M U T A T I O N S IN GENES OT~ THAN APP
CODON 717 MUTATIONS
ALTERED
/ APPMETABO ~LISM~ , ~ 9
~
~
B/A4 D E P O S I T I O N
P
~
NON-GENETIC (enviromental)
OTHER APP M U T A T I O N S D O ~ 'S SYNDROME TRISOMY APP
~ ? S
~ SENILE
|,
NE~OFIBRIL~Y T~GLES
I Y
NERVE C E L L DEATH
D~ENTIA
Fig.2.PossiblepathogeneticpathwaysforthecausesandprogressionofthepathologicalchangesofAhheimer'disease. s mon. No intraneuronal inclusions other than N F T were seen. Immunohistochemistry demonstrated a typical anti-PHF, anti-tau and anti-ubiquitin immunoreactivity to N F T and plaques also typically stained with anti-tau, anti-ubiquitin and anti-GFAP. Again, using immunochemical methods no intraneuronal inclusions other than N F T were seen. Anti-A4 immunostaining revealed severe congophilic angiopathy within meningeal vessels overlying cerebellar and occipital cortices though this was much less severe in other brain regions. These pathological changes (represented by Fig. 1) are thus entirely typical of AD and display no unusual characteristics. The implication of this present study is that this particular mutation within codon 717 of the APP molecule is probably pathogenic and leads to a pathological outcome that is entirely that of AD. This result appears to be the same in most of the other mutations of codon 717 [20, 21], though apparently not so in all [6, 9]. How the pathological cascade of AD is brought about by this mutation is not clear though it is likely that it is associated with some abberation in the metabolism of APP. The fact that there are (so far 3) different mutations at codon 717 implies that neither hydrophobicity nor bulk are critical to the altered processing. Moreover, it has been shown [10] that in the case of the val---)ile substitution, at least, no change in the rate of APP expression is associated with this defect. Hence it is possible that in some way the altered APP is prevented from being processed via normal metabolic pathways (which involve a cleavage across the flA4 sequence [4]) and is diverted along a subsidiary pathway which is perhaps normally inhibited but
which ultimately leads to the unusual and excessive formation and accumulation of fl/A4 peptide. Other familial forms of AD (not involving a codon 717 mutation or a mutation in other parts of the APP molecule), Down's syndrome (DS), as well as non-genetic (environmental) causes might all bring about the same, or a similar, APP processing defect and cause fl/A4 to accumulate (Fig. 2). Whether deposition of fl/A4, per se, is sufficient to trigger the rest of the pathological cascade (Fig. 2) is less clear since it is now well known that deposition offl/A4 can occur in the absence of neuritic changes and N F T formation in areas such as striatum [22] and cerebellum [11, 14, 23] in both AD and DS and even within the cerebral cortex and hippocampus in conditions other than AD (and DS) [13, 17, 19, 26]. Hence, PHF formation may proceed in parallel to, but not necessarily as a direct consequence of, fl/A4 formation. It is possible that it is a different fragment of the APP molecule, released during its cleavage that is responsible for, or modulates, PHF formation. Whatever the factor that triggers PHF formation might be, it seems clear that it is an entity that is specific for AD and perhaps more importantly one that is specifically produced by the cerebral cortex in AD, or if it is produced in other regions (e.g. cerebellum) it does not affect local neurones in the same way. The fact that the APP molecule is glycosylated [12] and observations that unusual and excessive accumulations of glycoproteins occur within the cerebral cortical, but not the cerebellar cortical, amyloid deposits, in AD and DS [14, 16, 18, 25] suggest that oligosaccharides, possibly derived from APE might mediate the neuritic changes.
228 1 Chartier-Harlin, M.C., Crawford, F., Houlden, H., Warren, A., Hughes, D., Fidani, L., Goate, A., Rossor, M., Roques, P., Hardy, J. and Mullan, M. Mutations at codon 717 of the ,8-amyloid precursor protein gene cause Alzheimer's disease, Nature, 353 (1991) 844-846. 2 Cross, R.B., Demonstration of neurofibrillary tangles in paraffin section a quick and simple method using Palmgren's technique, Med. Lab. Sci., 39 (1982) 67 69. 3 Davies, L., Wolska, B., Hilbich, C., Multhaup, G., Martins, R., Simms, G., Beyreuther, K. and Masters, C.L., A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathological techniques, Neurology 38 (1988) 1688-1693. 4 Esch, F.S., Helm, P.S., Beattie, E.C., Blancher, R.W., Culwell, A.R., Oltersdorf, T., McClure, D. and Ward, P.J., Cleavage of amyloid ,8 peptide during constitutive processing of its precursor, Science, 248 (1990) 1122- 1124. 5 Goate, A., Owen, M.J., James, L.A., Mullan, M.J., Rossor, M.N., Haynes, A.R., Farrall, M., Lai, L.Y.C., Roques, P., Williamson, R. and Hardy, J.A., Predisposing locus for Alzheimer's disease on chromosome 21, Lancet, i (1989) 352-355. 6 Goate, A., Chartier-Harlin, M.C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Gioffra, L., Haynes, A., Irving, N., James, L., Mant, R., Newton, P., Rooke, K., Roques, P., Talbot, C., Pericak-Vance, M., Roses, A., Williamson, R., Rossor, M., Owen, M. and Hardy, J.A., Segregation ofa missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease, Nature, 349 (1991) 704-706. 7 Goldgaber, D., Lerman, M.I., McBride, O.W., Saffioti, U. and Gajdusek, D.C., Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease, Science, 235 (1987) 877--880. 8 Haga, C., Yamaguchi, I., lkeda, K. and Kosaka, K., PAM modified silver stain for senile plaques: comparison with ,8 protein immunostaining, Dementia, 3 (1989) 417-422. 9 Hardy, J.A., Mullan, M., Chartier-Harlin, M.C. et al., Molecular classification of Alzheimer's disease, Lancet, 337 (1991 ) 1342-1342. 10 Harrison, P.J., Barton, A.J. and Pearson, R.C.A., Expression of amyloid ,8 protein precursor mRNAs in familial Alzheimer's disease, Neurorep., 2 (1991) 152 154. 11 Joachim, C.L., Morris, J.H. and Selkoe, D.J., Diffuse senile plaques occur commonly in the cerebellum in Alzheimer's disease, Am. J. Pathol., 135 (1989) 309 319. 12 Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J.M., Masters, C.L., Grzeschik, K.H., Multhaup, G., Beyreuther, K. and MullerHill, B., The precursor of Alzheimer's disease A4 protein resembles a cell surface receptor, Nature, 325 (1987) 733 736. 13 Mann, D.M.A. and Jones, D., Deposition of amyloid protein in the brains of persons with dementing disorders other than Alzheimer's disease and Down's syndrome, Neurosci. Lett., 109 (1990) 68 75. 14 Mann, D.M.A., Jones, D., Prinja, D. and Purkiss, M.S., The pre-
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