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α-Enolase reduces cerebrovascular Aβ deposits by protecting Aβ amyloid formation

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Abstract

Cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid β (Aβ) deposits and causes dementia and cerebral hemorrhage. Although α-enolase (ENO1) was shown to possess multifunctional roles, its exact functions in CAA pathogenesis have not been determined. In this study, we focused on ENO1, a well-known glycolytic enzyme, which was previously identified via a proteomic approach as an upregulated protein in brain samples from patients with Alzheimer's disease (AD). We utilized the thioflavin T fluorescence assay and transmission electron microscopy to monitor the effects of ENO1 on amyloid formation by Aβ peptides. We also cultured murine primary cerebrovascular smooth muscle cells to determine the effects of ENO1 on Aβ cytotoxicity. To investigate the effects of ENO1 in vivo, we infused ENO1 or a vehicle control into the brains of APP23 mice, a transgenic model of AD/CAA, using a continuous infusion system, followed by a cognitive test and pathological and biochemical analyses. We found that novel functions of ENO1 included interacting with Aβ and inhibiting its fibril formation, disrupting Aβ fibrils, and weakening the cytotoxic effects of these fibrils via proteolytic degradation of Aβ peptide. We also demonstrated that infusion of ENO1 into APP23 mouse brains reduced cerebrovascular Aβ deposits and improved cognitive impairment. In addition, we found that enzymatically inactivated ENO1 failed to inhibit Aβ fibril formation and fibril disruption. The proteolytic activity of ENO1 may thus underlie the enzyme’s cytoprotective effect and clearance of Aβ from the brain, and ENO1 may be a therapeutic target in CAA.

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Availability of data and materials

The datasets analyzed in this current study are available from the corresponding author on reasonable request.

Abbreviations

Aβ:

Amyloid β

APP:

Amyloid precursor protein

CAA:

Cerebral amyloid angiopathy

ENO1:

α-Enolase

H2O2 :

Hydrogen peroxide

PBS:

Phosphate-buffered saline

TEM:

Transmission electron microscopy

ThT:

Thioflavin T

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Acknowledgements

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

Funding

This research was supported by a Grant-in-Aid for Young Scientists (19K16919) from the Japan Society for the Promotion of Science (JSPS), a fund for the Promotion of Joint International Research (Fostering Joint International Research (A)) (19KK0410) from JSPS, the Japan Foundation of Applied Enzymology, Kanae Foundation for Life and Socio-Medical Science, The Uehara Memorial Foundation, Kobayashi Magobe Memorial Medical Foundation, Takeda Science Foundation, Daiwa Health Foundation, The Osaka Medical Research Foundation for Intractable Diseases, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and SENSHIN Medical Research Foundation.

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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, Kumamoto, 860-8556, Japan

    Yasuteru Inoue, Teruaki Masuda, Yohei Misumi, Toshiya Nomura & Mitsuharu Ueda

  2. Department of Biomedical Laboratory Sciences, Graduate School of Health Sciences, Kumamoto University, Kumamoto, Japan

    Masayoshi Tasaki

  3. Department of Amyloidosis Research, Nagasaki International University, Sasebo, Japan

    Yukio Ando

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  1. Yasuteru Inoue
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  2. Masayoshi Tasaki
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Contributions

YI, YA, and MU designed the experiments. YI contributed to writing the draft of the text and preparation of the figures. YI, MT, and TN performed the experiments, and TM and YM assisted with tissue analysis. YI wrote the main manuscript text and prepared the figures. All authors discussed the data and participated in the editing. MU supervised the study. All authors reviewed the manuscript.

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Correspondence to Yasuteru Inoue.

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Inoue, Y., Tasaki, M., Masuda, T. et al. α-Enolase reduces cerebrovascular Aβ deposits by protecting Aβ amyloid formation. Cell. Mol. Life Sci. 79, 462 (2022). https://doi.org/10.1007/s00018-022-04493-x

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