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Acta Neuropathologica

, Volume 134, Issue 4, pp 605–617 | Cite as

Sushi repeat-containing protein 1: a novel disease-associated molecule in cerebral amyloid angiopathy

  • Yasuteru Inoue
  • Mitsuharu UedaEmail author
  • Masayoshi Tasaki
  • Akari Takeshima
  • Akihito Nagatoshi
  • Teruaki Masuda
  • Yohei Misumi
  • Takayuki Kosaka
  • Toshiya Nomura
  • Mayumi Mizukami
  • Sayaka Matsumoto
  • Taro Yamashita
  • Hitoshi Takahashi
  • Akiyoshi Kakita
  • Yukio Ando
Original Paper

Abstract

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (Aβ) deposits and causes cerebral hemorrhage and dementia. The exact molecules that co-accumulate with cerebrovascular Aβ deposits are still not fully known. In our study here, we performed proteomic analyses with microdissected leptomeningeal arteries and cerebral neocortical arterioles from 8 cases with severe CAA, 12 cases with mild CAA, and 10 control cases without CAA, and we determined the levels of highly expressed proteins in cerebral blood vessels in CAA. We focused on sushi repeat-containing protein 1 (SRPX1), which is specifically expressed in CAA-affected cerebral blood vessels. Because SRPX1, which is known as a tumor suppressor gene, reportedly induced apoptosis in tumor cells, we hypothesized that SRPX1 may play an important role in Aβ-induced apoptosis in CAA. Immunohistochemical studies revealed that SRPX1 co-accumulated with Aβ deposits in cerebral blood vessels of all autopsied cases with severe CAA. In contrast, no SRPX1 co-accumulated with Aβ deposits in senile plaques. Furthermore, we demonstrated that both Aβ40 and Aβ42 bound to SRPX1 in vitro and enhanced SRPX1 expression in primary cultures of cerebrovascular smooth muscle cells. SRPX1 enhanced caspase activity induced by Aβ40. Knockdown of SRPX1, in contrast, reduced the formation of Aβ40 accumulations and the activity of caspase in cultured cerebrovascular smooth muscle cells. SRPX1 may thus be a novel molecule that is up-regulated in cerebrovascular Aβ deposits and that may increase Aβ-induced cerebrovascular degeneration in CAA.

Keywords

Amyloid β Cerebral amyloid angiopathy Cerebrovascular degeneration Cytotoxicity Proteomics Sushi repeat-containing protein 1 

Abbreviations

AD

Alzheimer’s disease

Amyloid β

ApoE

Apolipoprotein E

APP

Amyloid precursor protein

BSA

Bovine serum albumin

CAA

Cerebral amyloid angiopathy

CR

Congo red

ELISA

Enzyme-linked immunosorbent assay

HBSS

Hanks’ balanced salt solution

HSC-71

Heat shock cognate 71 kDa protein

HRP

Horseradish peroxidase

LCM

Laser capture microdissection

LC–MS/MS

Liquid chromatography–tandem mass spectrometry

PCR

Polymerase chain reaction

SAP

Serum amyloid P component

SRPX1

Sushi repeat-containing protein 1

Notes

Acknowledgements

We express our gratitude to Ms. Hiroko Katsura for her technical support during histopathological investigations. We are indebted to Ms. Judith B. Gandy for providing professional English editing of the manuscript.

Compliance with ethical standards

Funding

This research was supported by Grants-in-Aid for Science Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant Numbers 15K09318, 15H04841, 15K15195).

Conflict of interest

The authors have no conflicts of interest to disclose.

Supplementary material

401_2017_1720_MOESM1_ESM.xlsx (335 kb)
Supplementary material 1 (XLSX 335 kb)
401_2017_1720_MOESM2_ESM.pdf (2.2 mb)
Supplementary material 2 (PDF 2256 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Yasuteru Inoue
    • 1
  • Mitsuharu Ueda
    • 1
    Email author
  • Masayoshi Tasaki
    • 1
  • Akari Takeshima
    • 2
  • Akihito Nagatoshi
    • 1
  • Teruaki Masuda
    • 1
  • Yohei Misumi
    • 1
  • Takayuki Kosaka
    • 1
  • Toshiya Nomura
    • 1
  • Mayumi Mizukami
    • 1
  • Sayaka Matsumoto
    • 1
  • Taro Yamashita
    • 1
  • Hitoshi Takahashi
    • 2
  • Akiyoshi Kakita
    • 2
  • Yukio Ando
    • 1
  1. 1.Department of Neurology, Graduate School of Medical SciencesKumamoto UniversityKumamoto-CityJapan
  2. 2.Department of PathologyBrain Research Institute, Niigata UniversityNiigataJapan

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