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

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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.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

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

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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.

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Authors and Affiliations

  1. Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Chuo-ku, Honjo, Kumamoto-City, Kumamoto, 860-8556, Japan

    Yasuteru Inoue, Mitsuharu Ueda, Masayoshi Tasaki, Akihito Nagatoshi, Teruaki Masuda, Yohei Misumi, Takayuki Kosaka, Toshiya Nomura, Mayumi Mizukami, Sayaka Matsumoto, Taro Yamashita & Yukio Ando

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

    Akari Takeshima, Hitoshi Takahashi & Akiyoshi Kakita

Authors
  1. Yasuteru Inoue
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  2. Mitsuharu Ueda
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Corresponding author

Correspondence to Mitsuharu Ueda.

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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).

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The authors have no conflicts of interest to disclose.

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Inoue, Y., Ueda, M., Tasaki, M. et al. Sushi repeat-containing protein 1: a novel disease-associated molecule in cerebral amyloid angiopathy. Acta Neuropathol 134, 605–617 (2017). https://doi.org/10.1007/s00401-017-1720-z

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  • DOI: https://doi.org/10.1007/s00401-017-1720-z

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