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ALZHEIMER'S DISEASE AND TAU PROTEINS
1098 MOBILISATION OF LEAD FROM ADIPOSE TISSUE AND CISPLATIN THERAPY
SIR,-Dr EI-Sharkawi and colleagues (Aug 2, p 249) have found high levels of lead in the kidney and kidney area of patients after chemotherapy with cisplatin. They contend that the main area of accumulation is the skeleton and that "only the skeletal pool is large enough to provide the kidney burdens measured". Although El-Sharkawi et al are probably correct in concluding that "some of the bone lead is rapidly mobilised and accumulates temporarily in the kidney", they may not have considered a more obscure but no less substantial source of lead, the adipose tissue. Reports of lead in adipose tissue have been published.’ Barry’ noted the presence of lead at very low levels in both the omental and subcutaneous fat depots of men with a history of occupational exposure. These levels were deemed insignificant relative to those found in the bone. As part of a project sponsored by the Foundation for Advancements in Science and Education, we have measured lead by atomic absorption in the adipose tissue of 21 occupationally exposed men (painters). We found levels as high as 12 parts per million wet weight. The adipose tissue was aspirated from the hip.3 If 15% of the body weight of a standard 70 kg man is fat,’ the adipose tissue lead burden could be as high as 130 mg. EI-Sharkawi et al state that trauma, alcoholism, pregnancy, prolonged febrile illness, and neoplastic disorders increase bone turnover, and it is just these circumstances that mobilise fat stores in the body. Although we can find no reports of cisplatin mobilising fat stores, the possibility is a real one in the light of the stress that this treatment causes to the digestion and absorption of foods and of the emesis associated with carboplatin. Any such mobilisation would release the lead into circulation, and we propose that the mobilisation of lead from fat stores cannot be discounted in the temporary accumulation of lead in the kidney after chemotherapy with cisplatin. Office of Water, US Environmental Protection Agency, Washington, DC 20460, USA
WILLIAM L. MARCUS
Foundation for Advancements in Science and Education, Los Angeles, California
GERALD T. LIONELLI
ALZHEIMER’S DISEASE AND TAU PROTEINS
SiR,—Dr Iqbal and colleagues (Aug 23, p 421) demonstrate the role of the phosphorylation of tau proteins-a group of microtubule-associated proteins-in the defective assembly of brain tubulin into microtubules in Alzheimer’s disease. Several other groups have raised antisera against paired helical filament preparations; the antibody we raised was found on immunoblotting to contain anti-tau antibodies.’ In collaboration with Prof J. Nunez (Paris) we raised an antiserum against the tau proteins: this antiserum labelled selectively the tangles and abnormal neurites around the senile plaques’-3 on paraffin tissue sections in Alzheimer’s disease. These results were also presented as a poster at an international meeting in Belgium in 1985.4 Several other contributions have confirmed that tau, especially phosphorylated tau,S,6 may be an important component of the paired helical filaments observed in Alzheimer’s disease and some other related conditions.7-11 Having been studying microtubules and axonal transport for many years, we suggested12,13 that disturbances of microtubule assembly may be the cause of the abnormal axonal transport observed in Alzheimer’s disease. A role for microtubules and associated proteins in tangle formation has been suggested by others. Thus all recent data confirm a possible link between microtubules, the tau proteins required for their stability, and disturbed axoplasmic flow in Alzheimer’s disease. Immunocytochemical studies have shown that phosphorylated antigens belonging to other cytoskeletal proteins (eg, neurofilament side-arm proteins) can be detected on paired helical filaments, and interference with the transport of neurofilament has been hypothesised as a possible mechanism for axonal flow disturbances.14 These data have to be kept in mind in the understanding of the chemical nature of paired helical filaments. Since the first evidence of labelling of the tangles by an anti-tau antiserum was obtained in our laboratory, the absence of any mention of our results in Iqbal and colleagues’ paper is regrettable. Department of Pathology and University Hospital Erasme, Free University of Brussels, B-1070 Brussels, Belgium
JEAN-PIERRE BRION JACQUELINE FLAMENT-DURAND PIERRE DUSTIN
HealthMed Clinic,
DANNY LEE CURTIS
Los Angeles 1.
Barry PSI. A comparison of concentrations of lead in human tissues. Br J Ind Med
2.
Barry PSI. Concentrations of lead in the tissues of children. Br J Ind Med 1981; 38:
1975; 32: 119-39. 61-71.
SM, et al. A simple technique for fat biopsy of PBB-exposed individuals. Environ Health Perspect 1978; 23: 183-85. 4. Barry PSI, Mossman DB. Lead concentrations in human tissues. Br J Ind Med 1970; 2: 339-51. 5. Mitchell EP, Schein PS. Gastrointestinal toxicity of chemotherapeutic agents. Semin Oncol 1982; 9: 52-64. 3. Daum
CHOPSTICKS DYSPHAGIA
SiR,—As a daily user of chopsticks could I, on behalf of 1000 million users, comment on two cases of dysphagia following intake of food with chopsticks (Oct 11, p 866)? I suggest that these patients had dysphagia as a result of not doing what children are constantly reminded to do-namely, to bite and chew their food properly before swallowing. It had nothing to do with their use of chopsticks; millions of hamburgers are consumed everyday without the aid of a knife and fork. Watching my little nephew chopping and eating, noodles with his chopsticks I would like to query the statement that chopsticks cannot cut. Care should be taken when using chopsticks to eat any food with bones (fish, chicken, and duck) as these bones account for 824% of 2394 cases of foreign bodies in the
oesophagus.’ Department of Child Health, University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne NE2 4HH 1. Nandi
T. H. H. G. KOH
P, Ong GB. Foreign body in the oesophagus: Review of 2394 cases. Br J Surg 1978; 65: 5-9.
1. Brion JP, Passareiro H, Nunez J, Flament-Durand J. Mise en evidence immunologique de la proteine tau au niveau des lesions de degenerescence neurofibrillaires de la maladie d’Alzheimer. Arch Biol (Brux) 1985; 95: 229-35. 2. Brion JP, van den Bosch de Aguilar P, Flament-Durand J. Senile dementia of the Alzheimer type: morphological and immunocytochemical studies. In: Gispen WH, Traber J, eds. Senile dementia of Alzheimer type. Adv Appl Neurol Sci vol II, Berlin: Springer, 1985: 164-74. 3. Flament-Durand J, Bnon JP. Ultrastructural and immunohistochemical study of neurofibrillary tangles in Alzheimer’s disease. Pathol Res Pract 1985; 180: 267. 4. Bnon JP, Couck AM, Flament-Durand J. Microtubules and microtubule-associated proteins (MAPs) in Alzheimer’s disease. 3rd International Symposium on Microtubules and Microtubule Inhibitors (abstr)· 33. 5. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83: 4913-17. 6. Ihara Y, Nukina N, Miura R, Ogawara M. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer’s disease. J Biochem 1986; 99: 1807-10. 7. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM Microtubule-associated protein tau: a component of Alzheimer paired helical filaments. J Biol Chem 1986; 261: 6084-89. 8. Kosik KS, Joachim CL, Selkoe DJ. Microtubule-associated protein tau (&tgr;) is a major antigenic component of paired helical filaments in Alzheimer’s disease. Proc Natl Acad Sci USA 1986; 83: 4044-48. 9. Nukina N, Ihara Y. One of the antigenic determinants of paired helical filaments is related to tau proteins. J Biochem 1986; 99: 1541-44. 10. Wood JG, Mirra SS, Pollock NJ, Binder LI. Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (&tgr;). Proc Natl Acad Sci USA 1986; 83: 4043-44. 11. Yen SH, Dickson DW, Crowe A, Butler M, Shelanski ML. Alzheimer’s neurofibrillary tangles contain epitopes in common with the heat-stable microtubule associated proteins, tau and MAP2. Am J Pathol (in press). 12. Dustin P, Flament-Durand J. Disturbances of axoplasmic transport in Alzheimer’s disease. In: Weiss DG, Gorio A, eds. Axoplasmic transports and pathology. Berlin Springer, 1982· 131-36. 13. Dustin P. Microtubules, 2 ed. Berlin. Springer, 1984 14. Gajdusek DC. Hypothesis: Interference with axonal transport of neurofilament as a common pathogenic mechanism of certain diseases of the central nervous system. N Engl J Med 1985; 312: 714-19.
SIR,-Dr EI-Sharkawi and colleagues (Aug 2, p 249) have found high levels of lead in the kidney and kidney area of patients after chemotherapy with cisplatin. They contend that the main area of accumulation is the skeleton and that "only the skeletal pool is large enough to provide the kidney burdens measured". Although El-Sharkawi et al are probably correct in concluding that "some of the bone lead is rapidly mobilised and accumulates temporarily in the kidney", they may not have considered a more obscure but no less substantial source of lead, the adipose tissue. Reports of lead in adipose tissue have been published.’ Barry’ noted the presence of lead at very low levels in both the omental and subcutaneous fat depots of men with a history of occupational exposure. These levels were deemed insignificant relative to those found in the bone. As part of a project sponsored by the Foundation for Advancements in Science and Education, we have measured lead by atomic absorption in the adipose tissue of 21 occupationally exposed men (painters). We found levels as high as 12 parts per million wet weight. The adipose tissue was aspirated from the hip.3 If 15% of the body weight of a standard 70 kg man is fat,’ the adipose tissue lead burden could be as high as 130 mg. EI-Sharkawi et al state that trauma, alcoholism, pregnancy, prolonged febrile illness, and neoplastic disorders increase bone turnover, and it is just these circumstances that mobilise fat stores in the body. Although we can find no reports of cisplatin mobilising fat stores, the possibility is a real one in the light of the stress that this treatment causes to the digestion and absorption of foods and of the emesis associated with carboplatin. Any such mobilisation would release the lead into circulation, and we propose that the mobilisation of lead from fat stores cannot be discounted in the temporary accumulation of lead in the kidney after chemotherapy with cisplatin. Office of Water, US Environmental Protection Agency, Washington, DC 20460, USA
WILLIAM L. MARCUS
Foundation for Advancements in Science and Education, Los Angeles, California
GERALD T. LIONELLI
ALZHEIMER’S DISEASE AND TAU PROTEINS
SiR,—Dr Iqbal and colleagues (Aug 23, p 421) demonstrate the role of the phosphorylation of tau proteins-a group of microtubule-associated proteins-in the defective assembly of brain tubulin into microtubules in Alzheimer’s disease. Several other groups have raised antisera against paired helical filament preparations; the antibody we raised was found on immunoblotting to contain anti-tau antibodies.’ In collaboration with Prof J. Nunez (Paris) we raised an antiserum against the tau proteins: this antiserum labelled selectively the tangles and abnormal neurites around the senile plaques’-3 on paraffin tissue sections in Alzheimer’s disease. These results were also presented as a poster at an international meeting in Belgium in 1985.4 Several other contributions have confirmed that tau, especially phosphorylated tau,S,6 may be an important component of the paired helical filaments observed in Alzheimer’s disease and some other related conditions.7-11 Having been studying microtubules and axonal transport for many years, we suggested12,13 that disturbances of microtubule assembly may be the cause of the abnormal axonal transport observed in Alzheimer’s disease. A role for microtubules and associated proteins in tangle formation has been suggested by others. Thus all recent data confirm a possible link between microtubules, the tau proteins required for their stability, and disturbed axoplasmic flow in Alzheimer’s disease. Immunocytochemical studies have shown that phosphorylated antigens belonging to other cytoskeletal proteins (eg, neurofilament side-arm proteins) can be detected on paired helical filaments, and interference with the transport of neurofilament has been hypothesised as a possible mechanism for axonal flow disturbances.14 These data have to be kept in mind in the understanding of the chemical nature of paired helical filaments. Since the first evidence of labelling of the tangles by an anti-tau antiserum was obtained in our laboratory, the absence of any mention of our results in Iqbal and colleagues’ paper is regrettable. Department of Pathology and University Hospital Erasme, Free University of Brussels, B-1070 Brussels, Belgium
JEAN-PIERRE BRION JACQUELINE FLAMENT-DURAND PIERRE DUSTIN
HealthMed Clinic,
DANNY LEE CURTIS
Los Angeles 1.
Barry PSI. A comparison of concentrations of lead in human tissues. Br J Ind Med
2.
Barry PSI. Concentrations of lead in the tissues of children. Br J Ind Med 1981; 38:
1975; 32: 119-39. 61-71.
SM, et al. A simple technique for fat biopsy of PBB-exposed individuals. Environ Health Perspect 1978; 23: 183-85. 4. Barry PSI, Mossman DB. Lead concentrations in human tissues. Br J Ind Med 1970; 2: 339-51. 5. Mitchell EP, Schein PS. Gastrointestinal toxicity of chemotherapeutic agents. Semin Oncol 1982; 9: 52-64. 3. Daum
CHOPSTICKS DYSPHAGIA
SiR,—As a daily user of chopsticks could I, on behalf of 1000 million users, comment on two cases of dysphagia following intake of food with chopsticks (Oct 11, p 866)? I suggest that these patients had dysphagia as a result of not doing what children are constantly reminded to do-namely, to bite and chew their food properly before swallowing. It had nothing to do with their use of chopsticks; millions of hamburgers are consumed everyday without the aid of a knife and fork. Watching my little nephew chopping and eating, noodles with his chopsticks I would like to query the statement that chopsticks cannot cut. Care should be taken when using chopsticks to eat any food with bones (fish, chicken, and duck) as these bones account for 824% of 2394 cases of foreign bodies in the
oesophagus.’ Department of Child Health, University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne NE2 4HH 1. Nandi
T. H. H. G. KOH
P, Ong GB. Foreign body in the oesophagus: Review of 2394 cases. Br J Surg 1978; 65: 5-9.
1. Brion JP, Passareiro H, Nunez J, Flament-Durand J. Mise en evidence immunologique de la proteine tau au niveau des lesions de degenerescence neurofibrillaires de la maladie d’Alzheimer. Arch Biol (Brux) 1985; 95: 229-35. 2. Brion JP, van den Bosch de Aguilar P, Flament-Durand J. Senile dementia of the Alzheimer type: morphological and immunocytochemical studies. In: Gispen WH, Traber J, eds. Senile dementia of Alzheimer type. Adv Appl Neurol Sci vol II, Berlin: Springer, 1985: 164-74. 3. Flament-Durand J, Bnon JP. Ultrastructural and immunohistochemical study of neurofibrillary tangles in Alzheimer’s disease. Pathol Res Pract 1985; 180: 267. 4. Bnon JP, Couck AM, Flament-Durand J. Microtubules and microtubule-associated proteins (MAPs) in Alzheimer’s disease. 3rd International Symposium on Microtubules and Microtubule Inhibitors (abstr)· 33. 5. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83: 4913-17. 6. Ihara Y, Nukina N, Miura R, Ogawara M. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer’s disease. J Biochem 1986; 99: 1807-10. 7. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM Microtubule-associated protein tau: a component of Alzheimer paired helical filaments. J Biol Chem 1986; 261: 6084-89. 8. Kosik KS, Joachim CL, Selkoe DJ. Microtubule-associated protein tau (&tgr;) is a major antigenic component of paired helical filaments in Alzheimer’s disease. Proc Natl Acad Sci USA 1986; 83: 4044-48. 9. Nukina N, Ihara Y. One of the antigenic determinants of paired helical filaments is related to tau proteins. J Biochem 1986; 99: 1541-44. 10. Wood JG, Mirra SS, Pollock NJ, Binder LI. Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (&tgr;). Proc Natl Acad Sci USA 1986; 83: 4043-44. 11. Yen SH, Dickson DW, Crowe A, Butler M, Shelanski ML. Alzheimer’s neurofibrillary tangles contain epitopes in common with the heat-stable microtubule associated proteins, tau and MAP2. Am J Pathol (in press). 12. Dustin P, Flament-Durand J. Disturbances of axoplasmic transport in Alzheimer’s disease. In: Weiss DG, Gorio A, eds. Axoplasmic transports and pathology. Berlin Springer, 1982· 131-36. 13. Dustin P. Microtubules, 2 ed. Berlin. Springer, 1984 14. Gajdusek DC. Hypothesis: Interference with axonal transport of neurofilament as a common pathogenic mechanism of certain diseases of the central nervous system. N Engl J Med 1985; 312: 714-19.