Acta Neuropathol (1995) 90 : 547-551 9 Springer-Verlag 1995 I.A. Auer 9 M.L. Schmidt 9V.M.-Y. Lee 9B. Curry K. Suzuki 9R.-W. Shin 9P.G. Pentchev 9E.D. Carstea J.Q. Trojanowski Paired helical filament tau (PHFtau) in Niemann-Pick type C disease is similar to PHFtau in Alzheimer's disease Received: 2 May 1995 / Accepted: 16 August 1995 Abstract Niemann-Pick Type C disease (NPC) is a cho- lesterol storage disease with defects in the intracellular trafficking of exogenous cholesterol derived from low density lipoproteins. In NPC cases with a chronic pro- gressive course, neurofibrillary tangles (NFTs) that con- sist of paired helical filaments (PHFs) have been reported. To determine if NPC tangles contain abnormal tan pro- teins (known as PHFtau) similar to those found in Alzheimer's disease (AD) tangles, we examined the brains of five NPC cases by immunohistochemical and Western blot methods using a library of antibodies to de- fined epitopes of PHFtau. We show here that PHFtau in tangle-rich NPC brains is indistinguishable from PHFtau in AD brains. We speculate, that the generation of PHFtau in NPC may induce a cascade of pathological events that contribute to the widespread degeneration of neurons, and that these events may be similar in NPC and AD. Key words Cholesterol metabolism 9 Cytoskeleton 9 Dementia Introduction Niemann-Pick disease Type C (NPC) is a genetic disorder characterized by defects in the intracellular trafficking of exogenous cholesterol resulting in cholesterol storage in various organs [9, 10, 18]. The clinical spectrum of NPC is heterogeneous [4, 17]; however, in late onset cases the most common mode of presentation is an insidious onset dementia with progressive neurological deterioration, up- ward gaze paralysis and progressive gait ataxia. In addition to the neuronal storage, neurofibrillary tan- gles (NFTs) have been noted in these late onset NPC cases [6, 13, 16]. Since the NFTs in NPC contain abundant paired helical filaments (PHFs) on electron microscopy and they resemble the NFTs in classical Alzheimer's dis- ease (AD), we sought to determine if these NPC brains contained abnormal tan proteins (PHFtau) like those that form PHF in AD NFTs. This study showed that NPC brains contained PHFtau similar to that found in AD brains, thereby establishing a link between the formation of NFTs from PHFtau in NPC and AD. I.A. Auer (N~). B. Currey Department of Histopathology, Foothills Hospital, University of Calgary, 1403 29 St. NW, Calgary, Alberta, Canada T2N 2T9 M.L. Schmidt 9 V.M.-Y. Lee 9 J. Q. Trojanowski Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA K. Suzuki Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA R.-W. Shin Department of Neuropathology, Kyushu University, Fukuoka, Japan P.G. Pentchev 9 E.D. Carstea Developmental and Metabolic Neurology Branch, National Institute of Neurological Diseases and Stroke, NIH, Bethesda MD, USA Materials and methods The brains from each of the NPC patients were fixed in 10% for- malin and processed for paraffin embedding. In addition, portions of the brains were snap frozen and preserved for immunohisto- chemical and Western blot analysis. Multiple sections of the cere- bral and cerebellar cortex, white matter, hippocampus, thalamus, basal ganglia, pons, medulla, spinal cord and peripheral ganglia were stained with hematoxylin and eosin (H&E), Luxol fast blue (LFB), periodic acid-Schiff (PAS) and Bielschowsky silver stain. A summary of the key clinicopathological findings is provided in Table 1, and clinicopathological details of cases 3, 4, and 5 were published recently [16]. Immunohistochemical studies of formalin-fixed, paraffin-em- bedded sections of the NPC cases were conducted as described in several recent papers [1, 5, 8, 12, 14, 15] using the microwave anti- gen retrieval method [20]. Western blot studies of PHFtau ex- tracted from frozen samples of the NPC cases were performed as described earlier [1, 5, 8, 11, 12, 14, 15]. Sections of AD brains [11, 12] and extracts of PHFtau from AD brains [1, 5] were used as controls. PHFtau was detected in tissue sections and in Western