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Variable expression of microglial DAP12 and TREM2 genes in Nasu-Hakola disease

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Abstract

Nasu-Hakola disease (NHD) is a form of presenile dementia associated with sclerosing leukoencephalopathy and polycystic lipomembranous osteodysplasia. This extremely rare inherited disease is caused by mutations in either DAP12 or TREM2. The present study was designed to assess the relationship between DAP12/TREM2 genotype, mRNA and protein expression levels by both Western blotting and immunohistochemistry, and the tissue distribution and pathomorphological phenotype of the microglia. Molecular genetic testing performed in three NHD cases confirmed that two cases had mutations in DAP12 and that one case carried a mutation in TREM2. Protein levels were analyzed in four cases. Interestingly, significant DAP12 expression was found in numerous microglia in one NHD case with a homozygous DAP12 single-base substitution, and both real-time PCR and Western blotting confirmed the finding. In contrast, levels of both DAP12 and TREM2, respectively, were much lower in the other cases. Immunohistochemistry using established microglial markers revealed consistently mild activation of microglia in the cerebral white matter although there was no or only little expression of DAP12 in three of the NHD cases. The highly different expression of DAP12 represents the first description of such variable expressivity in NHD microglia. It raises important questions regarding the mechanisms underlying dementia and white matter damage in NHD.

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Acknowledgments

The authors would like to thank Drs. T Togo and N Aoki for supplying tissue samples. The expert technical assistance of Tomio Honma and Toshinori Nagai is gratefully acknowledged. This work was supported by a Grant-in-Aid for Scientific Research (C) (25430051) from the Ministry of Education, Culture, Supports, Science and Technology, Japan, and by a Grant-in-Aid from the Research Committee for Hereditary Cerebral Small Vessel Disease and Associated Disorders from the Ministry of Health, Labour and Welfare, Japan.

Ethical approval

This study was conducted with the approval of the Ethical Committees of Niigata University and Saitama Medical University.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Pathology, Saitama Medical University, 38 Morohongo, Iruma, Saitama, 350-0495, Japan

    Atsushi Sasaki & Kei Shioda

  2. Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan

    Akiyoshi Kakita

  3. Department of Brain Disease Research, Shinshu University School of Medicine, Matsumoto, Japan

    Kunihiro Yoshida

  4. Department of Neurology Brain Research Institute, Niigata University, Niigata, Japan

    Takuya Konno

  5. Department of Molecular Genetics Brain Research Institute, Niigata University, Niigata, Japan

    Takeshi Ikeuchi

  6. Department of Neurology, Mishima Hospital, Niigata, Japan

    Shintaro Hayashi

  7. Department of Neurology, Nagasaki Kawatana Medical Center, Nagasaki, Japan

    Hidenori Matsuo

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  1. Atsushi Sasaki
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Correspondence to Atsushi Sasaki.

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Supplementary Fig. 1

Microglial morphology and expression of microglial markers in the frontal white matter of NHD brains. In NHD case 1, higher magnification (HE staining) shows enlargement of the perivascular space (a), and immunostaining for CD68 (b), CD163 (c), and CD204 (d) reveals activated and phagocytic microglia, with frequent accumulation of the latter in the perivascular area. In the same case, a cluster of lipid-laden macrophages can be seen in the occipital white matter in the HE stained section (e) and following Iba1 immunohistochemistry (f). Loss of myelin, presence of axonal spheroids (g), and infiltration of microglia and macrophages labeled with antibodies against Iba1 (h) and MHC class II (i) are visible in NHD case 2. Primary magnification: ×20 (PDF 1,457 kb)

Supplementary Fig. 2

Quantification of Iba1-positive cells in the frontal cortex of NHD and control cases. Fourteen microscopic images of Iba1 staining (200× magnification) were acquired in each case from two NHD cases (case 1 and case 2) and two control subjects. Long horizontal lines represent mean values. Morphometric analysis of Iba1-immunostained sections of the NHD cases showed that the percentage (mean ± SD) of tissue area occupied by microglial cell bodies and processes was 8.42 ± 1.747. By contrast, in the control subjects without neurological disease, the average percentage of tissue area occupied by microglial cells was only 2.145 ± 0.56. (PDF 64 kb)

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Sasaki, A., Kakita, A., Yoshida, K. et al. Variable expression of microglial DAP12 and TREM2 genes in Nasu-Hakola disease. Neurogenetics 16, 265–276 (2015). https://doi.org/10.1007/s10048-015-0451-3

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