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Memantine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist, Attenuates Cerebral Amyloid Angiopathy by Increasing Insulin-Degrading Enzyme Expression

  • Yasuteru Inoue
  • Mitsuharu UedaEmail author
  • Teruaki Masuda
  • Yohei Misumi
  • Taro Yamashita
  • Yukio Ando
Article

Abstract

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (Aβ) deposits and causes cerebral hemorrhages and dementia in elderly people. Memantine is used in Alzheimer’s disease to inhibit the glutamatergic system by blocking N-methyl-d-aspartate receptors. Its therapeutic effects in CAA are unclear, however. Here, we used APP23 transgenic mice (CAA model) to investigate whether memantine has direct therapeutic effects on cerebrovascular Aβ deposits. We treated APP23 mice and age-matched wild-type littermates with memantine at ages 6–18 months. We counted the numbers of vessels with Aβ and hemosiderin deposits. We measured soluble and insoluble Aβ40 and Aβ42 levels and levels of amyloid precursor protein (APP), APP-processing enzymes (α-, β-, γ-secretase), and Aβ-degrading enzymes (insulin-degrading enzyme [IDE], neprilysin). Memantine reduced cerebrovascular Aβ and hemosiderin deposits in APP23 mice. Compared with controls, memantine-treated APP23 mice had reduced Aβ40 levels and increased levels of hippocampal and vascular IDE. Our results suggest that memantine reduces cerebrovascular Aβ deposits by enhancing Aβ-cleaving IDE expression. The clinical availability of memantine may allow its use as a novel therapeutic agent in CAA.

Keywords

Cerebral amyloid angiopathy Memantine Insulin-degrading enzyme 

Abbreviations

AD

Alzheimer’s disease

ADAM10

Anti-mouse disintegrin and metalloproteinase domain-containing protein 10

Amyloid β

ANOVA

Analysis of variance

APH-1

Anterior pharynx-defective 1

APP

Amyloid precursor protein

BACE1

β-site APP-cleaving enzyme 1

CAA

Cerebral amyloid angiopathy

ELISA

Enzyme-linked immunosorbent assay

GFAP

Glial fibrillary acidic protein

HBSS

Hanks’ balanced salt solution

HRP

Horseradish peroxidase

IDE

Insulin-degrading enzyme

MWM

Morris water maze

NMDA

N-Methyl-d-aspartate

NMDAR

NMDA receptor

PCR

Polymerase chain reaction

PEN2

Presenilin enhancer 2

PS1

Presenilin 1

PVDF

Polyvinylidene fluoride

Notes

Acknowledgments

We express our gratitude to Mrs. Hiroko Katsura and Mrs. 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 Grants-in-Aid for Science Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant numbers 15H04841, 17H06972, 18K07502).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neurology, Graduate School of Medical SciencesKumamoto UniversityKumamoto-CityJapan

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