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Ann Clin Transl Neurol. 2014 Aug;1(8):519-33. doi: 10.1002/acn3.79. Epub 2014 Jul 8.

Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid.

Author information

1
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.
2
Department of Neurology, Graduate School of Medicine, Kyoto University Kyoto, Japan ; Department of Pathology, National Cerebral and Cardiovascular Center Osaka, Japan.
3
Division of Clinical Neurosciences, Southampton General Hospital, Southampton University Hampshire, United Kingdom.
4
Department of Neurology, Graduate School of Medicine, Kyoto University Kyoto, Japan.
5
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.
6
Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Osaka, Japan.
7
Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School Charlestown, Massachusetts.
8
Department of Pathology, National Cerebral and Cardiovascular Center Osaka, Japan.
9
Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovation Kobe, Japan.
10
Amakusa Hospital Kumamoto, Japan.
11
Institute for Ageing and Health, NIHR Biomedical Research Building, Newcastle University, Campus for Ageing and Vitality Newcastle upon Tyne, United Kingdom.
12
Department of Neurology, Graduate School of Medicine, Kyoto University Kyoto, Japan ; Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center Osaka, Japan.

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.

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