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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University Kyoto, Japan ; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School Charlestown, Massachusetts.
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University Kyoto, Japan ; Department of Pathology, National Cerebral and Cardiovascular Center Osaka, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Division of Clinical Neurosciences, Southampton General Hospital, Southampton University Hampshire, United Kingdom.
authors.forename: Roxana O
authors.initials: RO
authors.lastname: Carare
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University Kyoto, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hase
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University Kyoto, Japan ; Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Osaka, Japan.
authors.forename: Yorito
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: Division of Clinical Neurosciences, Southampton General Hospital, Southampton University Hampshire, United Kingdom.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hawkes
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University Kyoto, Japan ; Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Osaka, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School Charlestown, Massachusetts.
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Terasaki
authors.affiliation: Department of Pathology, National Cerebral and Cardiovascular Center Osaka, Japan.
authors.forename: Hatsue
authors.initials: H
authors.lastname: Ishibashi-Ueda
authors.affiliation: Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovation Kobe, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Taguchi
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University Kyoto, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Amakusa Hospital Kumamoto, Japan.
authors.forename: Taihei
authors.initials: T
authors.lastname: Miyakawa
authors.affiliation: Institute for Ageing and Health, NIHR Biomedical Research Building, Newcastle University, Campus for Ageing and Vitality Newcastle upon Tyne, United Kingdom.
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
authors.affiliation: Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School Charlestown, Massachusetts.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.affiliation: Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School Charlestown, Massachusetts.
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University Kyoto, Japan ; Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center Osaka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara