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


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.


Cerebral amyloid angiopathy Memantine Insulin-degrading enzyme 



Alzheimer’s disease


Anti-mouse disintegrin and metalloproteinase domain-containing protein 10

Amyloid β


Analysis of variance


Anterior pharynx-defective 1


Amyloid precursor protein


β-site APP-cleaving enzyme 1


Cerebral amyloid angiopathy


Enzyme-linked immunosorbent assay


Glial fibrillary acidic protein


Hanks’ balanced salt solution


Horseradish peroxidase


Insulin-degrading enzyme


Morris water maze




NMDA receptor


Polymerase chain reaction


Presenilin enhancer 2


Presenilin 1


Polyvinylidene fluoride



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.


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.


  1. 1.
    Viswanathan A, Greenberg SM (2011) Cerebral amyloid angiopathy in the elderly. Ann Neurol 70:871–880. CrossRefGoogle Scholar
  2. 2.
    Esiri MM, Wilcock GK (1986) Cerebral amyloid angiopathy in dementia and old age. J Neurol Neurosurg Psychiatry 49:1221–1226. CrossRefGoogle Scholar
  3. 3.
    Mandybur TI (1975) The incidence of cerebral amyloid angiopathy in Alzheimer’s disease. Neurology 25:120–126. CrossRefGoogle Scholar
  4. 4.
    Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ (2003) Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 348:1333–1341. CrossRefGoogle Scholar
  5. 5.
    Rammes G, Danysz W, Parsons CG (2008) Pharmacodynamics of memantine: an update. Curr Neuropharmacol 6:55–78. CrossRefGoogle Scholar
  6. 6.
    Thomas SJ, Grossberg GT (2009) Memantine: a review of studies into its safety and efficacy in treating Alzheimer’s disease and other dementias. Clin Interv Aging 4:367–377. Google Scholar
  7. 7.
    Folch J, Busquets O, Ettcheto M, Sánchez-López E, Castro-Torres RD, Verdaguer E, Garcia ML, Olloquequi J et al (2018) Memantine for the treatment of dementia: a review on its current and future applications. J Alzheimers Dis 62:1223–1240. CrossRefGoogle Scholar
  8. 8.
    Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M et al (2007) Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27:796–807. CrossRefGoogle Scholar
  9. 9.
    Decker H, Lo KY, Unger SM, Ferreira ST, Silverman MA (2010) Amyloid-β peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3β in primary cultured hippocampal neurons. J Neurosci 30:9166–9171. CrossRefGoogle Scholar
  10. 10.
    Floden AM, Li S, Combs CK (2005) β-Amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor α and NMDA receptors. J Neurosci 25:2566–2575. CrossRefGoogle Scholar
  11. 11.
    Martinez-Coria H, Green KN, Billings LM, Kitazawa M, Albrecht M, Rammes G, Parsons CG, Gupta S et al (2010) Memantine improves cognition and reduces Alzheimer’s-like neuropathology in transgenic mice. Am J Pathol 176:870–880. CrossRefGoogle Scholar
  12. 12.
    Ray B, Banerjee PK, Greig NH, Lahiri DK (2010) Memantine treatment decreases levels of secreted Alzheimer’s amyloid precursor protein (APP) and amyloid beta (Aβ) peptide in the human neuroblastoma cells. Neurosci Lett 470:1–5. CrossRefGoogle Scholar
  13. 13.
    Alley GM, Bailey JA, Chen D, Ray B, Puli LK, Tanila H, Banerjee PK, Lahiri DK (2010) Memantine lowers amyloid-β peptide levels in neuronal cultures and in APP/PS1 transgenic mice. J Neurosci Res 88:143–154. CrossRefGoogle Scholar
  14. 14.
    Scholtzova H, Wadghiri YZ, Douadi M, Sigurdsson EM, Li YS, Quartermain D, Banerjee P, Wisniewski T (2008) Memantine leads to behavioral improvement and amyloid reduction in Alzheimer’s-disease-model transgenic mice shown as by micromagnetic resonance imaging. J Neurosci Res 86:2784–2791. CrossRefGoogle Scholar
  15. 15.
    Liu MY, Wang S, Yao WF, Zhang ZJ, Zhong X, Sha L, He M, Zheng ZH et al (2014) Memantine improves spatial learning and memory impairments by regulating NGF signaling in APP/PS1 transgenic mice. Neuroscience 273:141–151. CrossRefGoogle Scholar
  16. 16.
    Ettcheto M, Sánchez-López E, Gómez-Mínguez Y, Cabrera H, Busquets O, Beas-Zarate C, García ML, Carro E et al (2018) Peripheral and central effects of memantine in a mixed preclinical mice model of obesity and familial Alzheimer’s disease. Mol Neurobiol 55:7327–7339. CrossRefGoogle Scholar
  17. 17.
    Arac A, Brownell SE, Rothbard JB, Chen C, Ko RM, Pereira MP et al (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 94:13287–13292. CrossRefGoogle Scholar
  18. 18.
    Minkeviciene R, Banerjee P, Tanila H (2004) Memantine improves spatial learning in a transgenic mouse model of Alzheimer’s disease. J Pharmacol Exp Ther 311:677–682. CrossRefGoogle Scholar
  19. 19.
    Ueda M, Horibata Y, Shono M, Misumi Y, Oshima T, Su Y, Tasaki M, Shinriki S et al (2011) Clinicopathological features of senile systemic amyloidosis: an ante- and post-mortem study. Mod Pathol 24:1533–1544. CrossRefGoogle Scholar
  20. 20.
    Levites Y, Das P, Price RW, Rochette MJ, Kostura LA, McGowan EM et al (2006) Anti-Aβ42- and anti-Aβ40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model. J Clin Invest 116:193–201. CrossRefGoogle Scholar
  21. 21.
    Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, Tolnay M, Staufenbiel M et al (2001) Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci 21:1619–1627. CrossRefGoogle Scholar
  22. 22.
    Koldamova R, Staufenbiel M, Lefterov I (2005) Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem 280:43224–43235.
  23. 23.
    Huang SM, Mouri A, Kokubo H, Nakajima R, Suemoto T, Higuchi M et al (2006) Neprilysin-sensitive synapse-associated amyloid-β peptide oligomers impair neuronal plasticity and cognitive function. J Biol Chem 281:17941–17951.
  24. 24.
    Lefterov I, Fitz NF, Cronican A, Lefterov P, Staufenbiel M, Koldamova R (2009) Memory deficits in APP23/Abca1 +/− mice correlate with the level of Aβ oligomers. ASN Neuro 1:e00006. CrossRefGoogle Scholar
  25. 25.
    Nakamura T, Shinriki S, Jono H, Guo J, Ueda M, Hayashi M, Yamashita S, Zijlstra A et al (2015) Intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance and a slow-cycling state in bone marrow-disseminated tumor cells. Oncotarget 6:1008–1019. Google Scholar
  26. 26.
    Zhao G, Liu Z, Ilagan MX, Kopan R (2010) γ-Secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin. J Neurosci 30:1648–1656. CrossRefGoogle Scholar
  27. 27.
    Boulay AC, Saubaméa B, Declèves X, Cohen-Salmon M (2015) Purification of mouse brain vessels. J Vis Exp 105:e53208. Google Scholar
  28. 28.
    Bernstein HG, Ansorge S, Riederer P, Reiser M, Frölich L, Bogerts B (1999) Insulin-degrading enzyme in the Alzheimer’s disease brain: prominent localization in neurons and senile plaques. Neurosci Lett 263:161–164. CrossRefGoogle Scholar
  29. 29.
    Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA et al (2003) Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer’s disease is associated with the apolipoprotein E-ε4 allele. Am J Pathol 162:313–319. CrossRefGoogle Scholar
  30. 30.
    Gao W, Eisenhauer PB, Conn K, Lynch JA, Wells JM, Ullman MD, McKee A, Thatte HS et al (2004) Insulin degrading enzyme is expressed in the human cerebrovascular endothelium and in cultured human cerebrovascular endothelial cells. Neurosci Lett 371:6–11. CrossRefGoogle Scholar
  31. 31.
    Morelli L, Llovera RE, Mathov I, Lue LF, Frangione B, Ghiso J, Castaño EM (2004) Insulin-degrading enzyme in brain microvessels: proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy. J Biol Chem 279:56004–56013.
  32. 32.
    Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ (2000) Neurons regulate extracellular levels of amyloid β-protein via proteolysis by insulin-degrading enzyme. J Neurosci 20:1657–1665. CrossRefGoogle Scholar
  33. 33.
    Miller BC, Eckman EA, Sambamurti K, Dobbs N, Chow KM, Eckman CB, Hersh LB, Thiele DL (2003) Amyloid-β peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc Natl Acad Sci U S A 100:6221–6226. CrossRefGoogle Scholar
  34. 34.
    Stargardt A, Gillis J, Kamphuis W, Wiemhoefer A, Kooijman L, Raspe M, Benckhuijsen W, Drijfhout JW et al (2013) Reduced amyloid-β degradation in early Alzheimer’s disease but not in the APPswePS1dE9 and 3xTg-AD mouse models. Aging Cell 12:499–507. CrossRefGoogle Scholar
  35. 35.
    Du J, Chang J, Guo S, Zhang Q, Wang Z (2009) ApoE 4 reduces the expression of Aβ degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons. Neurosci Lett 464:140–145. CrossRefGoogle Scholar
  36. 36.
    Jarvis MF, Murphy DE, Williams M (1987) Quantitative autoradiographic localization of NMDA receptors in rat brain using [3H]CPP: comparison with [3H] TCP binding sites. Eur J Pharmacol 141:149–152CrossRefGoogle Scholar
  37. 37.
    Texidó L, Martín-Satué M, Alberdi E, Solsona C, Matute C (2011) Amyloid β peptide oligomers directly activate NMDA receptors. Cell Calcium 49:184–190. CrossRefGoogle Scholar
  38. 38.
    De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST et al (2007) Aβ oligomers induce neuronal oxidative stress through an N-methyl-d-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 282:11590–11601.
  39. 39.
    Szegedi V, Juhász G, Budai D, Penke B (2005) Divergent effects of Aβ1-42 on ionotropic glutamate receptor-mediated responses in CA1 neurons in vivo. Brain Res 1062:120–126. CrossRefGoogle Scholar
  40. 40.
    Prelli F, Castaño E, Glenner GG, Frangione B (1988) Differences between vascular and plaque core amyloid in Alzheimer’s disease. J Neurochem 51:648–651. CrossRefGoogle Scholar
  41. 41.
    Suzuki N, Iwatsubo T, Odaka A, Ishibashi Y, Kitada C, Ihara Y (1994) High tissue content of soluble beta 1-40 is linked to cerebral amyloid angiopathy. Am J Pathol 145:452–460Google Scholar

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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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