Browse by author
Lookup NU author(s): Dr Yoshiki HaseORCiD, Professor Raj KalariaORCiD, Dr Masafumi Ihara
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Objective: Brain amyloidosis is a key feature of Alzheimer's disease (AD). It also incorporates cerebrovascular amyloid beta (A beta) 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 A beta 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 A beta metabolism in transgenic mice (Tg-SwDI mice) as a model of cerebrovascular beta-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 A beta(1-40), and rescued cognitive deficits in Tg-SwDI mice. Although cilostazol decreased endogenous A beta 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 A beta metabolism is likely to facilitate A beta 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(s): 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
Publication type: Article
Publication status: Published
Journal: Annals of Clinical and Translational Neurology
Year: 2014
Volume: 1
Issue: 8
Pages: 519-533
Print publication date: 01/08/2014
Online publication date: 08/07/2014
Acceptance date: 02/06/2014
Date deposited: 26/07/2018
ISSN (electronic): 2328-9503
Publisher: Wiley-Blackwell Publishing, Inc.
URL: https://doi.org/10.1002/acn3.79
DOI: 10.1002/acn3.79
Altmetrics provided by Altmetric
