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Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid

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Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid. / Maki, Takakuni; Okamoto, Yoko; Carare, Roxana O. et al.
In: Annals of Clinical and Translational Neurology, Vol. 1, No. 8, 01.08.2014, p. 519-533.

Research output: Contribution to Journal/MagazineJournal articlepeer-review

Harvard

Maki, T, Okamoto, Y, Carare, RO, Hase, Y, Hattori, Y, Hawkes, CA, Saito, S, Yamamoto, Y, Terasaki, Y, Ishibashi-Ueda, H, Taguchi, A, Takahashi, R, Miyakawa, T, Kalaria, RN, Lo, EH, Arai, K & Ihara, M 2014, 'Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid', Annals of Clinical and Translational Neurology, vol. 1, no. 8, pp. 519-533. https://doi.org/10.1002/acn3.79

APA

Maki, T., Okamoto, Y., Carare, R. O., Hase, Y., Hattori, Y., Hawkes, C. A., Saito, S., Yamamoto, Y., Terasaki, Y., Ishibashi-Ueda, H., Taguchi, A., Takahashi, R., Miyakawa, T., Kalaria, R. N., Lo, E. H., Arai, K., & Ihara, M. (2014). Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid. Annals of Clinical and Translational Neurology, 1(8), 519-533. https://doi.org/10.1002/acn3.79

Vancouver

Maki T, Okamoto Y, Carare RO, Hase Y, Hattori Y, Hawkes CA et al. Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid. Annals of Clinical and Translational Neurology. 2014 Aug 1;1(8):519-533. doi: 10.1002/acn3.79

Author

Maki, Takakuni ; Okamoto, Yoko ; Carare, Roxana O. et al. / Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid. In: Annals of Clinical and Translational Neurology. 2014 ; Vol. 1, No. 8. pp. 519-533.

Bibtex

@article{640a958819ff41c7a0e87767f399401e,
title = "Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid",
abstract = "Objective: Brain amyloidosis is a key feature of Alzheimer's disease (AD). It also incorporates cerebrovascular amyloid β (Aβ) in the form of cerebral amyloid angiopathy (CAA) involving neurovascular dysfunction. We have recently shown by retrospective analysis that patients with mild cognitive impairment receiving a vasoactive drug cilostazol, a selective inhibitor of phosphodiesterase (PDE) III, exhibit significantly reduced cognitive decline. Here, we tested whether cilostazol protects against the disruption of the neurovascular unit and facilitates the arterial pulsation-driven perivascular drainage of Aβ in AD/CAA. Methods: We explored the expression of PDE III in postmortem human brain tissue followed by a series of experiments examining the effects of cilostazol on Aβ metabolism in transgenic mice (Tg-SwDI mice) as a model of cerebrovascular β-amyloidosis, as well as cultured neurons. Results: We established that PDE III is abnormally upregulated in cerebral blood vessels of AD and CAA subjects and closely correlates with vascular amyloid burden. Furthermore, we demonstrated that cilostazol treatment maintained cerebral hyperemic and vasodilative responses to hypercapnia and acetylcholine, suppressed degeneration of pericytes and vascular smooth muscle cells, promoted perivascular drainage of soluble fluorescent Aβ1-40, and rescued cognitive deficits in Tg-SwDI mice. Although cilostazol decreased endogenous Aβ production in cultured neurons, C-terminal fragment of amyloid precursor protein expression was not altered in cilostazol-treated Tg-SwDI mice. Interpretation: The predominant action of cilostazol on Aβ metabolism is likely to facilitate Aβ clearance due to the sustained cerebrovascular function in vivo. Our findings mechanistically demonstrate that cilostazol is a promising therapeutic approach for AD and CAA.",
author = "Takakuni Maki and Yoko Okamoto and Carare, {Roxana O.} and Yoshiki Hase and Yorito Hattori and Hawkes, {Cheryl A.} and Satoshi Saito and Yumi Yamamoto and Yasukazu Terasaki and Hatsue Ishibashi-Ueda and Akihiko Taguchi and Ryosuke Takahashi and Taihei Miyakawa and Kalaria, {Raj N.} and Lo, {Eng H.} and Ken Arai and Masafumi Ihara",
year = "2014",
month = aug,
day = "1",
doi = "10.1002/acn3.79",
language = "English",
volume = "1",
pages = "519--533",
journal = "Annals of Clinical and Translational Neurology",
issn = "2328-9503",
publisher = "John Wiley and Sons Ltd",
number = "8",

}

RIS

TY - JOUR

T1 - Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid

AU - Maki, Takakuni

AU - Okamoto, Yoko

AU - Carare, Roxana O.

AU - Hase, Yoshiki

AU - Hattori, Yorito

AU - Hawkes, Cheryl A.

AU - Saito, Satoshi

AU - Yamamoto, Yumi

AU - Terasaki, Yasukazu

AU - Ishibashi-Ueda, Hatsue

AU - Taguchi, Akihiko

AU - Takahashi, Ryosuke

AU - Miyakawa, Taihei

AU - Kalaria, Raj N.

AU - Lo, Eng H.

AU - Arai, Ken

AU - Ihara, Masafumi

PY - 2014/8/1

Y1 - 2014/8/1

N2 - Objective: Brain amyloidosis is a key feature of Alzheimer's disease (AD). It also incorporates cerebrovascular amyloid β (Aβ) in the form of cerebral amyloid angiopathy (CAA) involving neurovascular dysfunction. We have recently shown by retrospective analysis that patients with mild cognitive impairment receiving a vasoactive drug cilostazol, a selective inhibitor of phosphodiesterase (PDE) III, exhibit significantly reduced cognitive decline. Here, we tested whether cilostazol protects against the disruption of the neurovascular unit and facilitates the arterial pulsation-driven perivascular drainage of Aβ in AD/CAA. Methods: We explored the expression of PDE III in postmortem human brain tissue followed by a series of experiments examining the effects of cilostazol on Aβ metabolism in transgenic mice (Tg-SwDI mice) as a model of cerebrovascular β-amyloidosis, as well as cultured neurons. Results: We established that PDE III is abnormally upregulated in cerebral blood vessels of AD and CAA subjects and closely correlates with vascular amyloid burden. Furthermore, we demonstrated that cilostazol treatment maintained cerebral hyperemic and vasodilative responses to hypercapnia and acetylcholine, suppressed degeneration of pericytes and vascular smooth muscle cells, promoted perivascular drainage of soluble fluorescent Aβ1-40, and rescued cognitive deficits in Tg-SwDI mice. Although cilostazol decreased endogenous Aβ production in cultured neurons, C-terminal fragment of amyloid precursor protein expression was not altered in cilostazol-treated Tg-SwDI mice. Interpretation: The predominant action of cilostazol on Aβ metabolism is likely to facilitate Aβ clearance due to the sustained cerebrovascular function in vivo. Our findings mechanistically demonstrate that cilostazol is a promising therapeutic approach for AD and CAA.

AB - Objective: Brain amyloidosis is a key feature of Alzheimer's disease (AD). It also incorporates cerebrovascular amyloid β (Aβ) in the form of cerebral amyloid angiopathy (CAA) involving neurovascular dysfunction. We have recently shown by retrospective analysis that patients with mild cognitive impairment receiving a vasoactive drug cilostazol, a selective inhibitor of phosphodiesterase (PDE) III, exhibit significantly reduced cognitive decline. Here, we tested whether cilostazol protects against the disruption of the neurovascular unit and facilitates the arterial pulsation-driven perivascular drainage of Aβ in AD/CAA. Methods: We explored the expression of PDE III in postmortem human brain tissue followed by a series of experiments examining the effects of cilostazol on Aβ metabolism in transgenic mice (Tg-SwDI mice) as a model of cerebrovascular β-amyloidosis, as well as cultured neurons. Results: We established that PDE III is abnormally upregulated in cerebral blood vessels of AD and CAA subjects and closely correlates with vascular amyloid burden. Furthermore, we demonstrated that cilostazol treatment maintained cerebral hyperemic and vasodilative responses to hypercapnia and acetylcholine, suppressed degeneration of pericytes and vascular smooth muscle cells, promoted perivascular drainage of soluble fluorescent Aβ1-40, and rescued cognitive deficits in Tg-SwDI mice. Although cilostazol decreased endogenous Aβ production in cultured neurons, C-terminal fragment of amyloid precursor protein expression was not altered in cilostazol-treated Tg-SwDI mice. Interpretation: The predominant action of cilostazol on Aβ metabolism is likely to facilitate Aβ clearance due to the sustained cerebrovascular function in vivo. Our findings mechanistically demonstrate that cilostazol is a promising therapeutic approach for AD and CAA.

U2 - 10.1002/acn3.79

DO - 10.1002/acn3.79

M3 - Journal article

AN - SCOPUS:84909592312

VL - 1

SP - 519

EP - 533

JO - Annals of Clinical and Translational Neurology

JF - Annals of Clinical and Translational Neurology

SN - 2328-9503

IS - 8

ER -