Abstract
Niemann-Pick disease type C (NPC) is an autosomal recessive disease, belonging to a clinically heterogeneous group of lipid storage diseases, distinguished by a unique error in cellular trafficking of exogenous cholesterol, associated with lysosomal accumulation of unesterified cholesterol. Unlike Niemann-Pick disease types A and B, there is no primary genetic defect in sphingomyelinase in NPC. During the routine neuropathological study of NPC patients, we found neurofibrillary tangles (NFT) in a series of cases with a slowly progressive chronic course. These were not associated with β-amyloid deposits. The NFT were most frequent in the orbital gyrus, cingulate gyrus and entorhinal region of the cerebral cortex, but were also frequently found in the basal ganglia, thalamus and hypothalamus. In one of the most severely affected case, the NFT were even found in the neurons in the inferior olivary nucleus and in the spinal cord. The NFT were immunostained with Alz 50, and cosisted of paired helical filaments. The distribution of the neurons bearing the NFT was generally similar to that of the swollen storage neurons, and storage neurons often contained NFT in their perikarya and/or in the meganeurites. However, neurons with NFT could be noted without swollen perikarya. The coexistence of neuronal storage and NFT in NPC without amyloid deposits suggests that perturbed cholesterol metabolism and/or lysosomal membrane trafficking may play a role in the formation of NFT, and that amyloid deposits are not necessarily the prerequisite for NFT formation. The results of our study also suggest that NFT formation may be a rather nonspecific cellular reaction of neurons to certain slowly progressive metabolic perturbations of an as yet undefined nature.
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Autio-Harmainen H, Oldfors A, Sourander P, Renlund M, Dammert K, Simila S (1988) Neuropathology of Salla disease. Acta Neuropathol (Berl) 75: 481–490
Chou SM, Thompson HG (1970) Electron microscopy of storage cytosomes in Kuf's disease. Arch Neurol 23: 489–501
Elleder M, Jirasek A (1981) Neuropathology of various types of Niemann-Pick disease. Acta Neuropathol (Berl) [Suppl] VII: 201–203
Elleder M, Jirasek A (1983) Niemann-Pick disease: report on a symposium held in Hlava's Institute of Pathology, Charles University, Prague, 2–3 September 1982. Acta Univ Carol [Med] (Praha) 29: 259–167
Elshourbagy NA, Liao WS, Mahley RW, Taylor JM (1985) Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissue of rats and marmosets. Proc Natl Acad Sci USA 82: 203–207
Fink JK, Filling-Katz MR, Sokol J, Cogan DG, Pikus A, Sonies B, Soong B, Pentchev PG, Comly ME, Brady RO, Barton NW (1989) Clinical spectrum of Niemann-Pick disease type C. Neurology 39: 1040–1049
Ghetti B, Tagliavini F, Masters CL, Beyreuther R, Giaccone G, Verga L, Farlow MR, Conneally FM, Dlouhy SR, Azzarelli B, Bugiani O (1989) Gerstmann-Straussler-Scheinker disease. II. Neurofibrillary tangles and plaques with PrP-amyloid coexist in an affected family. Neurology 39: 1453–1461
Halliday WC, Chudley AE (1989) 18q-syndrome: neurofibrillary tangles without neuritic plaques. J Neuropathol Exp Neurol 45: 308
Harzer K, Schlote W, Peiffer J, Benz HU, Anzil AP (1978) Neurovisceral lipidosis compatible with Niemann-Pick disease type C: morphological and biochemical studies of late infantile case and enzyme and lipid assays in a prenatal case of the same family. Acta Neuropathol (Berl) 43: 97–104
Higashi Y, Murayama S, Pentchev GP, Suzuki K (1991) Pathology of Niemann-Pick type C: studies of murine mutant. In: Ikuta F (ed) Neuropathology in brain research. Elsevier, Amsterdam, pp 85–102
Hof PR, Knabe R, Bovier R, Bouras C (1991) Neuropathological observation in a case of autism presenting with self-injury behavior. Acta Neuropathol 82: 321–326
Hof PR, Bouras C, Buee L, Delacourte A, Perl DP, Morrison JH (1994) Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer's disease cases. Acta Neuropathol 85: 23–30
Horoupian D, Yang SS (1978) Paired helical filaments in neurovisceral lipidosis (juvenile dystonic lipidosis). Ann Neurol 4: 404–411
Hulette CM, Earl NL, Anthony DC, Crain BJ (1992) Adult onset Niemann-Pick disease type C presenting with dementia and absent organomegaly. Clin Neuropathol 11: 293–297
Hyman BT, Van Hoesen GW, Wolozin BL, Davies P, Kromer LJ, Damasio AR (1988) Alz 50 antibody recognizes Alzheimer-related neuronal changes. Ann Neurol 23: 371–379
Hyman BT, Tanzi RE, Marzloff K, Barbour R, Schenk D (1992) Kunitz protease inhibitor-containing amyloid β protein precursor immunoreactivity in Alzheimer's disease. J Neuropathol Exp Neurol 51: 76–83
Kiuchi A, Otsuka N, Namba Y, Nakano I, Tomonaga M (1991) Presenile appearance of abundant Alzheimer's neurofibrillary tangles without senile plaques in the brain in myotonic dystrophy. Acta Neuropathol 80: 1–5
Kornfeld MM (1972) Generalized lipofuscinosis (generalized Kuf's disease). J Neuropathol Exp Neurol 31: 668–681
Lowenthal AC, Cummings JF, Wenger DA, Thrall MA, Wood PA, Lathunta A de (1990) Feline sphingolipidosis resembling Niemann-Pick disease type C. Acta Neuropathol 81: 189–197
Mahley RW (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240: 622–630
Mandybur TI (1990) The distribution of Alzherimer neurofibrillary tangles and gliosis in chronic subacute sclerosing panencephalitis. Acta Neuropathol 80: 307–310
McQuaid S, Allen IV, McMahon J, Kirk J (1994) Association of measles virus with neurofibrillary tangles in subacute sclerosing panencephalitis: a combined in situ hybridization and immunocytochemical investigation. Neuropathol Appl Neurobiol 20: 103–110
Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzeimer's disease and Kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res 541: 163–166
Pentchev PG, Comly ME, Kruth HS, Tokoro T, Butler J, Sokol J, Filling-Katz M, Quirk JM, Marshall DC, Patel S, Vanier MT, Brady RO (1987) Group C Niemann-Pick disease: faulty regulation of low density lipoprotein uptake and cholesterol storage in cultured fibroblasts. FASEB J 1: 40–47
Pentchev PG, Vanier MT, Suzuki K, Patterson MC (1995) Niemann-Pick disease type C: a cellular cholesterol lipidosis. In: Scriber CR, Beaudet AL, Sly WS, Valle D (eds) Metabolic basis of inherited disease, 7th edn. McGraw-Hill, New York (in press)
Popovitch ER, Wisniewski HM, Barcikowska M, Silverman W, Bancher CE, Sersen E, Wen GY (1990) Alzheimer neuropathology in non-Down's syndrome mentally retarded adults. Acta Neuropathol 80: 362–367
Sokol J, Blanchette-Mackie J, Kruth HS, Dwyer NK, Amenda LM, Butler JD, Robinson E, Patel S, Brady RO, Comly ME, Vanier MT, Pentchev PG (1988) Type C Niemann-Pick disease. Lysosomal accumulation and defective intracellular mobilization of low density lipoprotein cholesterol. J Biol Chem 263: 3411–3417
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer's disease. Proc Natl Acad Sci USA 90: 1977–1981
Strittmatter WJ, Weisgraber KH, Goedert M et al (1994) Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer's disease brain are related to apolipoprotein E genotype. Exp Neurol 125: 163–171
Tabaton M, Mandybur TI, Perry G, Onorato M, Autilio-Gambetti L, Gambetti P (1989) The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition. Ann Neurol 26: 771–778
Vanier MT, Rodriguez-Lafrasse C, Rousson R, Duthel S, Harzer K, Pentchev PG, Revol A, Louisot P (1991) Type C Niemann-Pick disease: biochemical aspects and phenotypic heterogeneity. Dev Neurosci 13: 307–314
Wisniewska K, Jervis GS, Moretz RC, Wisniewski HM (1979) Alzheimer neurofibrillary tangles in disease other than senile and pre-senile dementia. Ann Neurol 5: 288–294
Wolzin BL, Pruchnicki A, Dickson DW, Davies P (1986) A neuronal antigen in the brain of Alzheimer's pateints. Science 232: 648–650
Yamaguchi H, Haga C, Hirai S, Nakazata Y, Kosaka K (1990) Distinctive, rapid, and easy labeling of diffuse plaques in the Alzheimer brains by a new methanamine silver stain. Acta Neuropathol 79: 569–572
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Part of this study was presented at the Annual Meeting of the Canadian Association of Neuropathologists, Whistler, BC, Canada, September 1993
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Suzuki, K., Parker, C.C., Pentchev, P.G. et al. Neurofibrillary tangles in Niemann-Pick disease type C. Acta Neuropathol 89, 227–238 (1995). https://doi.org/10.1007/BF00309338
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DOI: https://doi.org/10.1007/BF00309338