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Isoform transition from four-repeat to three-repeat tau underlies dendrosomatic and regional progression of neurofibrillary pathology

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Abstract

Regional progression of neurofibrillary tangles (NFTs) around the hippocampus was traced on thick sections double immunofluorolabeled with RD3 and RD4 antibodies, specific for three- and four-repeat tau, respectively. As reported, the cubic density of all tau-positive neurons was predominant in the entorhinal cortex and cornu ammonis (CA)1, and decreased progressively to the CA2–4 subregions. Among the three isoform profiles (RD3+/4−, RD3+/4+, and RD3−/4+), this regional gradient was replicated with RD3+/4− and RD3+/4+ neurons, while RD3−/4+ neurons exhibited the reverse gradient. Comparison of the subregion pairs confirmed a consistent profile shift along this gradient in every case regardless of the abundance of NFTs. To clarify the underlying mechanism of this regional profile shift, intraneuronal intensity of RD3 and RD4 immunoreactivity (IR) was quantified. Although their intensities were both lower in dendrites than in the soma, this gradient was steeper with RD4, leaving RD3 IR in dendrites. Dendritic arborization was abundant in RD3−/4+ pretangles, attenuated in RD3+/4+ neurons, and further attenuated in RD3+/4− ghost tangles. These findings suggest that dendritic RD4 IR retracts first, leaving RD3 IR in the dendrites. Taken together, this dendrite-oriented retraction initiates the gradual shift from RD3−/4+ pretangle neurons to RD3+/4− ghost tangles by way of RD3+/4+ NFTs. This intraneuronal profile shift may be a basis for the regional gradation featured by the similar profile shift during progression of NFT pathology.

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Acknowledgments

This study is supported by Grants-in-Aid for Scientific Research (22500325) from the Ministry of Education, Culture, Sports, Science, and Technology, Grant from Japan Foundation for Neuroscience and Mental Health, the Mitsui Life Social Welfare Foundation, and the Tokyo Metropolitan Institute of Medical Science project “Mechanism for Early Diagnosis and Prevention of Parkinson’s disease.” The authors are grateful to Professor Hiroshi Oyama, Department of Clinical Information Engineering, Health Services Science, School of Public Health, Graduate School of Medicine, The University of Tokyo and Dr. Akihiko Morita, Division of Neurology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan for their advice in the statistical analyses and to Ms Ayako Nakamura for her excellent technical assistance.

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Authors and Affiliations

  1. Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8509, Japan

    Makoto Hara & Toshiki Uchihara

  2. Division of Neurology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan

    Makoto Hara & Satoshi Kamei

  3. Department of Pathology, Nakano General Hospital, 4-59-16 Chuo, Nakano-ku, Tokyo, 164-8607, Japan

    Katsuiku Hirokawa

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Correspondence to Toshiki Uchihara.

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401_2013_1097_MOESM1_ESM.jpg

Supplementary material 1 (JPEG 7,825 kb) Supplementary Fig. 1: RD3–/4+ pretangle-predominant region (case 6, CA3). A 2 × 4 tiling of a high-resolution unit (1,024 × 1,024 pixels) to encompass the X–Y surface of 1,452 μm × 767 μm of a double-labeled section. RD3−/4+ pretangles (c, green, arrowheads) were frequent in this subregion, while RD3+/4+ NFTs (c, yellow, empty triangles) and RD3+/4− ghost tangles (c, red, arrows) were rare. (bar = 100 μm, a green/RD4, b red/RD3, c merged)

401_2013_1097_MOESM2_ESM.jpg

Supplementary material 2 (JPEG 10079 kb) Supplementary Fig. 2: RD3+/4− ghost tangle-predominant region (case 7, CA1). A 3 × 4 tiling of a high-resolution unit (1,024 × 1,024 pixels) to encompass the X–Y surface of 1,460 μm × 1,113 μm of a double-labeled section. RD3+/4− ghost tangles (c, red, arrows) were frequent in this subregion, while RD3+/RD4+ NFTs (c, yellow, empty triangles) and RD3−/4+ pretangles (c green, arrowheads) were rare. (bars = 100 μm, a green/RD4, b red/RD3, c merged)

Supplementary material 3 (JPEG 2762 kb)

Supplementary material 4 (JPEG 2029 kb)

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Hara, M., Hirokawa, K., Kamei, S. et al. Isoform transition from four-repeat to three-repeat tau underlies dendrosomatic and regional progression of neurofibrillary pathology. Acta Neuropathol 125, 565–579 (2013). https://doi.org/10.1007/s00401-013-1097-6

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