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Acta Neuropathologica

, Volume 117, Issue 2, pp 125–136 | Cite as

Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies

  • Tetsuaki AraiEmail author
  • Ian R. A. Mackenzie
  • Masato Hasegawa
  • Takashi Nonoka
  • Kazhuhiro Niizato
  • Kuniaki Tsuchiya
  • Shuji Iritani
  • Mitsumoto Onaya
  • Haruhiko Akiyama
Original Paper

Abstract

Phosphorylated and proteolytically cleaved TDP-43 is a major component of the ubiquitin-positive inclusions in the most common pathological subtype of frontotemporal lobar degeneration (FTLD-U). Intracellular accumulation of TDP-43 is observed in a subpopulation of patients with other dementia disorders, including Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). However, the pathological significance of TDP-43 pathology in these disorders is unknown, since biochemical features of the TDP-43 accumulated in AD and DLB brains, especially its phosphorylation sites and pattern of fragmentation, are still unclear. To address these issues, we performed immunohistochemical and biochemical analyses of AD and DLB cases, using phosphorylation-dependent anti-TDP-43 antibodies. We found a higher frequency of pathological TDP-43 in AD (36–56%) and in DLB (53–60%) than previously reported. Of the TDP-43-positive cases, about 20–30% showed neocortical TDP-43 pathology resembling the FTLD-U subtype associated with progranulin gene (PGRN) mutations. Immunoblot analyses of the sarkosyl-insoluble fraction from cases with neocortical TDP-43 pathology showed intense staining of several low-molecular-weight bands, corresponding to C-terminal fragments of TDP-43. Interestingly, the band pattern of these C-terminal fragments in AD and DLB also corresponds to that previously observed in the FTLD-U subtype associated with PGRN mutations. These results suggest that the morphological and biochemical features of TDP-43 pathology are common between AD or DLB and a specific subtype of FTLD-U. There may be genetic factors, such as mutations or genetic variants of PGRN underlying the co-occurrence of abnormal deposition of TDP-43, tau and α-synuclein.

Keywords

Phosphorylation Fragmentation Frontotemporal lobar degeneration Progranulin Tau Alpha-synuclein TDP-43 

Notes

Acknowledgments

We thank Ms. H. Kondo, Ms. Y. Izumiyama, Ms. C. Haga and Ms. M. Luk for their excellent technical assistance. This research was supported by a Grant-in-Aid for Scientific Research (C) (to TA), a Grant-in-Aid for Scientific Research on Priority Areas—Research on Pathomechanisms of Brain Disorders (to MH), a Grant-in-Aid for Scientific Research (B) (to MH) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a grant from the Canadian Institutes of Health Research (grant # 74580) (to IM) and a grant from the Pacific Alzheimer Research Foundation (to IM).

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Tetsuaki Arai
    • 1
    Email author
  • Ian R. A. Mackenzie
    • 2
  • Masato Hasegawa
    • 3
  • Takashi Nonoka
    • 3
  • Kazhuhiro Niizato
    • 4
  • Kuniaki Tsuchiya
    • 5
  • Shuji Iritani
    • 6
  • Mitsumoto Onaya
    • 7
  • Haruhiko Akiyama
    • 1
  1. 1.Department of PsychogeriatricsTokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical ResearchTokyoJapan
  2. 2.Department of PathologyVancouver General HospitalVancouverCanada
  3. 3.Department of Molecular NeurobiologyTokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical ResearchTokyoJapan
  4. 4.Department of PsychiatryTokyo Metropolitan Matsuzawa HospitalTokyoJapan
  5. 5.Department of Laboratory Medicine and PathologyTokyo Metropolitan Matsuzawa HospitalTokyoJapan
  6. 6.Department of PsychiatryNagoya University Graduate School of MedicineNagoyaJapan
  7. 7.Department of NeuropsychiatryNational Shimofusa Mental HospitalChibaJapan

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